Complex Gene−Chemical Interactions: Hepatic ... - ACS Publications

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Complex Gene-Chemical Interactions: Hepatic Uroporphyria As a Paradigm Andrew G. Smith*,† and George H. Elder‡ MRC Toxicology Unit, Hodgkin Building, UniVersity of Leicester, Lancaster Road, Leicester LE1 9HN, U.K., and Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff UniVersity, Cardiff CF14 4XN, U.K. ReceiVed August 25, 2009

Many toxicological disorders, in common with numerous human diseases, are probably the consequence of multigene interactions with a variety of chemical and physiological factors. The importance of genetic factors may not be obvious initially from association studies because of their complexity and variable penetrance. The human disease, porphyria cutanea tarda (PCT), is a skin disease caused by the photosensitizing action of porphyrins arising secondary to the decreased activity of an enzyme of heme biosynthesis, uroporphyrinogen decarboxylase (UROD), in the liver. It is triggered by idiosyncratic hepatic interaction between genetic factors and chemicals such as alcohol, estrogenic drugs, and polyhalogenated aromatics. PCT and its animal models are known collectively as the hepatic uroporphyrias. There is strong evidence for the participation of iron in the pathogenesis of these conditions. Mouse models have been used to explore the relative importance of a variety of agents such as 2,3,7,8-tetrachlorodibenzop-dioxin (TCDD), alcohol, and iron in the development of uroporphyria and to elucidate the mechanism of the depression of hepatic UROD activity. Mutations of the UROD and hemochromatosis (HFE) genes are genetic factors in some PCT patients which can be mimicked in mice heterozygous for the Hfe and Urod null genes. Association studies of uroporphyria induced by TCDD or hexachlorobenzene with DNA markers in mouse intercrosses have shown the participation of other, unknown, genetic factors in addition to the strong influence of the Ahr gene. The pathogenesis of hepatic uroporphyrias exemplifies the complexity of the interactions between chemical and genetic factors that can contribute to the hepatotoxicity of chemicals. Contents 1. Introduction 1.1. Complex Gene-Environment Interactions 1.2. Idiosyncratic Liver Toxicity 2. Disorders of Heme Metabolism 3. Porphyria Cutanea Tarda 4. Chemical-Induced Uroporphyria 4.1. Human Uroporphyria 4.2. Experimental Uroporphyria in Animals 5. Role of Iron Metabolism 6. Genetic Complexity 6.1. Genetic Factors in Humans 6.2. Genetic Variation in Experimental Uroporphyria 6.3. Search for Susceptibility Genes in Mice 6.4. Overview 7. Consequence of Gene-Chemical Interaction 8. Conclusions

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1. Introduction Over recent decades, many gene-drug interactions have been reported (1, 2). For instance, interindividual differences in the response to the drugs debrisoquine and isoniazid were shown to be the consequences of variant alleles of the CYP2D6 and NAT2 genes, respectively, that in humans are responsible for oxidation and N-acetylation of the drugs (3, 4). This led to the * To whom correspondence should be addressed. E-mail: [email protected]. † University of Leicester. ‡ Cardiff University.

identification of many other examples of interindividual differences in responses to drugs which could often be interpreted as the consequence of polymorphisms in the genes for drug metabolism enzymes, such as the cytochrome P450 enzymes, glutathione transferases, N-acetyl transferases, methyl transferases, alcohol dehydogenases, and flavin monoxygenases, as well as transport proteins (1, 2). This huge body of research has been an important aspect of drug development leading to explanations of interindividual and interethnic group variation in drug efficacies, which might be exploited in therapy, and also contribute to the understanding of idiosyncratic adverse drug actions (1). It is often assumed that these polymorphisms (defined in humans as >1% incidence) represent highly penetrant monogenic traits. Understanding of polymorphisms pertinent to the metabolism of chemicals in general, whether of environmental, nutritional, occupational, intentional, or accidental origins, has been proposed as fundamental to processes of risk assessment (5). 1.1. Complex Gene-Environment Interactions. In aspects of medicine other than pharmacology and toxicology, gene polymorphisms and rarer variants have been associated with propensities to develop diseases, such as cancer, hypertension, cardiovascular diseases, Alzheimer’s disease, Parkinsonism, and diabetes (6-13). However, sometimes the strong associations between genetic variants and propensities for disease found in initial reports have become much weaker after meta-analyses of combined studies (14, 15). In fact, for most complex diseases there are interactions of many genetic factors with so-called environmental factors (that can include life style and nutrition)

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Figure 1. Spectrum of the influences of genes and environment determining pathological responses in individuals triggered by chemicals and drugs. Few interindividual variations in responses to a toxic agent in humans are likely to be solely dependent on genetic variability and not influenced by nutrition and lifestyle. Conversely, most toxic responses are probably dependent, to a greater or lesser extent, on genetic variability.

which vary considerably in their relevant contributions (Figure 1) (16). A variety of genetic components may each make only a small contribution. Even in many classical monogenic diseases, the phenotype may be influenced by additional factors. For the same disease, the penetrance of predisposing genes and the triggering environmental factors may differ between individuals, although resulting in a similar phenotype. Understanding the polymorphisms of predisposing genes and quantifying their contribution in any individual, are difficult tasks for the prediction of susceptibility and risk. The contribution of environmental factors may be dominant (17, 18). Such scenarios are probably important in many cases of idiosyncratic liver toxicity. 1.2. Idiosyncratic Liver Toxicity. One of the most common reasons for the failure of a lead compound in drug development and of adverse effects of medicines already in use is the development of toxic hepatic responses that seem to have no obvious explanation, i.e., idiosyncratic liver toxicity (19-21). Similar idiosyncratic effects probably also occur with illegal drugs and dietary supplements. For drugs such as bromfenac and troglitazone, this has led to their withdrawal from the market, and others have had their use restricted or warnings issued. Polymorphisms or rare variants in genes for phase I and II metabolic pathway enzymes, leading to differing enzymic activities, are potential candidates to explain idiosyncratic reactions; although the mode of action and metabolism of the drugs per se are not necessarily the reasons for toxicity (22-24). Genetic variation in genes for drug transporters, receptors, transcription factors, ion channels, cytokine action, cell death, and regeneration are also known to play their part (1, 20, 25, 26). Although methods for the rapid analysis of SNPs and other variants are now widely available, the relative rarity of idiosyncratic drug-induced liver disease makes identifying all of the genetic factors associated with liver injury a major enterprise. The hepatic effects of many of the known genes likely to be involved, singly or in simple combinations, can be explored in animals using knockout technology, although this is not the same as studying rare adverse effects in patients or using mutants with protein changes equivalent to those seen in humans (27). Many host specific factors can also be involved such as hepatitis C, the influence of alcohol consumption (affecting ALDH and CYP2E1 expression), obesity (causing steatosis), and nutrition (e.g., lowering glutathione levels) as well as the sex of the patient (21). Such factors may be associated with genetic variants in

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themselves that are, as yet, unexplored. For instance, hepatic iron status in patients is known to contribute to alcoholic liver disease, steatohepatitis in moderate obesity, chronic viral hepatitis, and end stage liver disease (28). New genes associated with iron metabolism have been discovered (29), but in mice, studies showed that genetically variable hepatic iron levels were not associated with iron genes that had been previously identified (30, 31). The aim of this review is to demonstrate this complexity of interactions between susceptibility genes and chemical factors as exemplified by disorders of hepatic heme metabolism, in particular, the group of disorders known as hepatic uroporphyrias that includes the human disease, porphyria cutanea tarda (PCT), and related conditions in laboratory animals.

2. Disorders of Heme Metabolism The synthesis of heme and its subsequent breakdown are fundamental processes in the normal physiological operation of the liver and other nonerythroid tissues (Figure 2). In humans, a number of monogenic disorders of heme metabolism illustrate the importance of interaction between inherited and endogenous or external factors in provoking clinically overt disease (32). One such disorder, Gilbert’s syndrome, results from reduced glucuronidation of the heme break down product bilirubin with subsequent elevated levels in plasma. It is a common condition, often considered benign because of a polymorphism (UGT1A1*28) in the promoter region of the UDP-glucuronosyltransferase (UGT) 1A1 gene (Figure 2). Unfortunately, some drugs, such as the antiretroviral protease inhibitor atazanavir, inhibit UGT 1A1. In patients with Gilbert’s syndrome, this can result in severe hyperbilrubinemia, liver toxicity, and perhaps predisposition to cancer (33, 34), and may involve additional variants of the UGT1A1 and other UGT genes (34, 35). Other examples come from the group of disorders of heme synthesis known as porphyrias. These comprise eight separate disorders, each of which results from abnormal function of a different enzyme of the pathway; in most porphyrias, this abnormality is the consequence of an inherited defect in the corresponding gene (32, 36, 37). Three porphyrias (AIP, HCP, and VP; see Figure 2) are characterized clinically by the sudden onset of life-threatening neurovisceral attacks associated with up-regulation of the rate limiting enzyme of hepatic heme synthesis, 5-aminolevulinate synthase (ALAS1), and increased synthesis of the neurotoxin, ALA. In VP and HCP, skin lesions may occur, caused by photosensitization of the skin by porphyrins produced in the liver, concurrently with the acute attacks or independently. These three disorders are inherited in an autosomal dominant pattern; in each disease, the activity of one of the enzymes of heme biosynthesis is decreased to half-normal because of mutations on one allele that markedly decrease or abolish enzyme activity. However, only a minority of those who inherit half-normal enzyme activity ever develop symptoms. Precipitation of most acute attacks appears to require exposure to a drug or hormonal or nutritional factors, all of which act through a complex network of receptors to induce ALAS1 activity (38). The likelihood of developing this response appears to vary between individuals, which suggests that other genetic factors may be involved in determining susceptibility. The other porphyrias, with one important exception, are either autosomal recessive or, in one recently described disorder, X-linked dominant (37, 39). In these disorders, affected individuals are nearly always symptomatic. The important exception, PCT, is by far the commonest form of porphyria. This disease exemplifies the consequence of a variety of

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Figure 2. Scheme of hepatic heme synthesis and metabolism. ALAS1, 5-aminolevulinate synthase; ALAD, 5-aminolevulinate dehydratase; HMBS, hydroxymethylbilane synthase; UROS, uroporphyrinogen III synthase; UROD, uroporphyrinogen decarboxylase; CPOX, coproporphyrinogen III oxidase; PPOX, protoporphyin IX oxidase; FECH, ferrochelatase; HMOX, heme oxygenase; BLVRA, biliverdin reductase; UGT1A1, UDP glucuronosyltransferase 1A1. Negative feedback control of the first enzyme in the pathway, ALAS1, as a consequence of a depleted regulatory heme pool, balances the flow of precursors for heme formation with demand for cytochromes etc. (38). Inactivation of UROD is triggered by alcohol and estrogens in porphyria cutanea tarda (PCT) and by polyhalogenated aromatic chemicals such as HCB and TCDD, as well as by iron in the uroporphyria in experimental laboratory animals. Other enzymes in the pathway are selectively inhibited by chemicals such as lead, porphyrogenic herbicides. and allyl and acetylenic chemicals, via a variety of mechanisms. In humans, decreased activities of HMBS, CPOX. and PPOX, due to mutations in their genes, gives rise to the genetic diseases acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP), respectively. These disorders are often precipitated by drugs and other stimuli and involve marked negative feedback up-regulation of hepatic ALAS1 activity (38). In contrast, up-regulation of ALAS1 is modest under the chronic conditions of uroporphyria in PCT and experimentally in rodents.

interactions between genetic and other factors, many of which can be reproduced in animals, and can be viewed as a paradigm of complex gene-chemical interactions leading to toxic sequelae.

3. Porphyria Cutanea Tarda Porphyria cutanea tarda (PCT) is a skin disease in which porphyrins cause photosensitization secondary to their over production in the liver. The disorder is commonly characterized by fragile skin, superficial erosions, subepidermal bullae, hypertrichosis, and patchy pigmentation, on areas of skin exposed to sunlight such as the face and the back of hands (40, 41). Other lesions include milia, scarring and, less frequently, sclerodermatous plaques. Patients are usually middleaged or older, and though in the past were mainly male, in northern Europe and the USA nearly as many women as men are now affected. PCT is characterized biochemically by increased formation of uroporphyrin and other porphyrins derived by oxidation of the porphyrinogen substrates of uroporphyrinogen decarboxylase (UROD), secondary to decreased activity of this enzyme in the liver (Figure 3). Sufficient overproduction of porphyrins to cause symptoms does not usually occur until hepatic UROD activity is 30% or less of the mean control activity. UROD converts asymmetric uroporphyrinogen III, which is formed enzymically from 1-hydroxymethylbilane, to coproporphyrinogen III that is then processed in three further steps to heme (Figure 2). Active UROD in the cytosol consists of a homodimer of proteins to sequentially remove four carboxyl groups from uroporphyrinogen (42-45). Unlike most decarboxylases, UROD does not require a cofactor. The symmetrical isomer I, formed chemically from 1-hydroxymethylbilane, that is not a precursor of heme is

also decarboxylated. Because of the potential for heme depletion in the liver as a result of low UROD activity, a feedback derepression of the regulatory enzyme ALAS1 expression may occur, via a regulatory heme pool, increasing levels of precursors of the heme pathway and potentiating the accumulation of porphyrins. However, the increase in ALAS1 activity is markedly less than is seen in the autosomal dominant acute porphyrias (Figure 2) and often within normal limits, probably because the chronic nature of the condition may require only modest increases to cause an effect in the long term. Biopsies of the liver in PCT show marked fluorescence when viewed under ultraviolet A light (UVA) because of the high concentrations of uroporphyrin in the tissue (Figure 3), and microscopy shows characteristic birefringent, needle-shaped crystals of uroporphyrin. Histopathological examination of the liver usually shows only modest changes including mild fatty infiltration, patchy focal necrosis, and inflammation of portal tracts. Cirrhosis is present in a minority of patients (41). Specific forms of hepatocellular injury, not obvious histopathologically, may be involved, and it is of interest that PCT patients have a greater risk of hepatocellular cancer than those with other forms of cirrhosis (46, 47). Siderosis is almost always present; uroporphyrin and ferritin iron often occur together in individual hepatocytes (48). An autoimmune response may contribute to hepatic injury, and an antiliver antibody has been detected in the serum of PCT patients (49). PCT can be divided into different types by measurement of UROD activity in erythrocytes and by mutational analysis of the UROD gene (50, 52, 53). In most western countries, about 75% of patients have sporadic (Type I) PCT with reduced activity only in the liver and no family history of the disease.

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Figure 3. Action of uroporphyrinogen decarboxylase (UROD) and alternative oxidation of the substrate to uroporphyrin causing symptoms of uroporphyria. In circumstances in which UROD is inhibited by the action of polyhalogenated chemicals such as 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD), polyhalogenated biphenyls (PCBs), and hexachlorobenzene (HCB) or in porphyria cutanea tarda (PCT), the porphyrinogen substrates are oxidized to uroporphyrin III and its isomer I which then accumulate causing liver damage and skin photosensitivity. Porphyrins fluoresce red when exposed to UV light. The inset shows a fluorescent liver from a mouse treated with TCDD (133), and similar observations are made with liver biopsies from PCT patients.

In these patients, no mutations have been detected in the coding or promoter sequences of the UROD gene, and protein expression is approximately normal. Rarely, more than one patient with these features is found in the same family (Type III), but the basis for this inheritance pattern has not been established. The remaining 25% or so of patients have an autosomal dominant disorder (Type II) with decreased UROD activity in all tissues caused by mutations in the UROD gene. Over 50 mutations in the UROD gene have now been identified in Type II PCT, mostly in exons 5-10 which encode 75% of the protein. These mutations act through various mechanisms to markedly reduce or abolish UROD activity, thus decreasing activities in the liver, erythrocytes, and other tissues to around 50% of normal (51). However, this decrease by itself is not sufficient to cause clinically overt PCT, and further, factors that are common to all types of PCT, and probably act through a common mechanism, appear to be required to decrease UROD activity below the threshold at which symptoms appear (40, 41). A number of common environmental agents act as risk factors for the development of both types of PCT, but the mechanisms are still not fully understood despite many investigations. Regular consumption of moderate amounts of alcohol has long been known to be the most common chemical/drug factor associated with PCT, although there appears to be no dose relationship. Less than 2% of alcoholics with cirrhosis develop PCT (54). An increasing number of cases of PCT are associated with estrogen usage in contraception and replacement therapy (55, 56). Some studies suggest that smoking may be a risk factor, but this could be associated with alcohol consumption (56). Strong association with hepatitis C infection has been reported and weaker association with hepatitis B and HIV (41). Curiously, among other conditions, greater than random incidence of PCT has also been reported in patients with type 2 diabetes or chronic renal disease treated by hemodialysis (57, 58). All

these chemical and other environmental factors may be subject to genetic variability in their influence, and one commonality might be that they are associated with aspects of iron homeostasis (see section 5).

4. Chemical-Induced Uroporphyria Hepatic uroporphyria also occurs in humans and laboratory animals as a consequence of exposure to certain chemicals, especially those polyhalogenated aromatics that are ligands for the aryl hydrocarbon receptor (AHR). 4.1. Human Uroporphyria. Chronic hepatic porphyria became of interest to toxicologists when several thousand individuals were poisoned in Turkey in the late 1950s by accidentally consuming wheat contaminated with the antifungal seed dressing, hexachlorobenzene (HCB). Many developed clinical and other features of PCT, notably hirsutism in affected children (59-65). Most of the affected were children, and symptoms took years to recede even after the identification and withdrawal of HCB. This episode is one of the classic cases in toxicology of mass poisoning and is still not fully understood. Skin lesions, hypertrichosis, pigmentation, scarring, and partial loss of phalanges were particularly severe probably due to both the potent nature of HCB and the continual exposure to strong sunlight and nutritional circumstances. Even so, of those that had ingested HCB probably only 10% were affected, and in preliminary studies, marked influence of age, sex, and family were reported. Urine was dark red-brown because of the presence of uroporphyrin, and biopsy of the liver showed the characteristic red fluorescence when viewed under UV light, whereas the bone marrow did not (66). Many patients had hepatomegaly, and of the few examined histopathologically, cirrhosis or hydropic and granular degeneration of hepatocytes were reported. In some patients the porphyria seems to have

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persisted for many years (63). Full details are summarized elsewhere (62, 67, 68). Lower exposure of other populations to HCB has been associated with irregularities in porphyrin excretion but usually without symptoms of overt PCT (69-72). Exposure to 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD) and to other polyhalogenated dibenzo-p-dioxins and dibenzofurans, at relatively high doses, have also been associated with PCTlike symptoms or elevated urinary excretion of porphyrins in some, but not all, episodes of contamination in the workplace or accidental exposure (62, 67, 73-79). At Seveso in Italy, many people were exposed to TCDD following an accident in a herbicide factory, but there seemed to be no direct correlation between the development of chloracne, the most unequivocal sign of poisoning by these chemicals in humans, and uroporphyria suggesting that in humans the former response is the more sensitive end point of toxicity (80). Similarly, a family poisoned by a mixture of polychlorinated dioxins and furans that were accidentally present in olive oil developed chloracne but showed no increase in urinary porphyrins. In contrast, uroporphyria developed after the same oil mixture was administered to mice (81). Likewise, among people poisoned by polychlorinated biphenyls (PCBs) and polybrominated biphenyls (PBBs), disturbances of porphyrin metabolism have been detected by levels and patterns of the porphyrins excreted in urine, but clinical porphyria manifested by cutaneous symptoms of PCT is rare (62, 68, 82-85). 4.2. Experimental Uroporphyria in Animals. HCB fed repeatedly to rats and rabbits at high doses causes massive hepatic uroporphyria with many similarities to the symptoms observed in PCT and the related porphyria caused by HCB in Turkey (86-89) (Figure 3). Livers usually exhibit steatosis and necrosis, especially in the centrilobular regions, and proliferation of the smooth endoplamic reticulum. As in PCT, crystalline inclusions of uroporphyrin are observed in the parenchyma. Among other species, quail appear very sensitive to HCB (90), whereas hamsters are resistant (Smith, A.G., unpublished observations). Lower chlorinated benzenes may also cause minor disturbances of heme metabolism but never to the degree observed with HCB (91). Mixtures of PCBs and PBBs, as exemplified by Aroclor 1254 and Firemaster, respectively, also cause marked hepatic uroporphyria (62, 67, 92-98). TCDD is a powerful inducer of porphyria in rats, unlike in humans, but it is necessary to use low doses to avoid death from systemic toxicity before uroporphyria develops (99, 100). Female rats are markedly more sensitive than males to the porphyrogenic effects of these chemicals, although the latter sex are sensitized by the coadministration of estrogens (98, 101-104). In mice, even a single dose of TCDD and similar chemicals causes uroporphyria in susceptible strains such as C57BL/6J and C57BL/10ScSn (Figure 3) (105-108). Interestingly, although mice appeared at first to be resistant to HCB, this is overcome by preloading animals with iron (109). Because TCDD and analogues are ligands of the AHR, it has been proposed that gene expression associated with this transcription factor is a likely mechanistic route leading to UROD inhibition in rodents (110, 111). This was confirmed using Ahr gene knockout mice (112). As to the particular gene expression involved, CYP1A2 is one gene product regulated by the AHR that appears to be essential in mice for uroporphyria development (113-115), although expression of this cytochrome at only a low, but critical, level seems required (116). However, it may not be the only AHR-regulated gene involved. The clinical and experimental evidence described above demonstrates that a diverse range of factors can trigger or

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enhance human and experimental uroporphyrias. The chemicalinduced uroporphyrias have been used extensively as models for PCT to investigate the mechanism. A common feature is a marked progressive decrease in UROD enzyme activity (Figure 3).

5. Role of Iron Metabolism Another central feature linking PCT with experimental uroporphyrias is strong evidence for a critical role of iron. Clinical evidence supports the view that at least normal hepatic iron stores are necessary for the development of PCT (40, 41). Nonheme iron levels in the liver or body iron stores are elevated in 60-65% of patients, but iron overload per se is mild to moderate in most people with active PCT, and only 15-20% of porphyria patients have severe iron overload. PCT has been reported in patients with secondary iron overload (117) or, rarely, clinically overt genetic hemochromatosis. Importantly, depletion of hepatic iron by repeated phlebotomy is an effective treatment for PCT and returns hepatic UROD activity toward basal levels, even in patients with normal total body iron stores (118-121). Alcohol may affect the accumulation or homeostasis of iron in the liver, perhaps by increasing intestinal absorption (54). The high frequency of PCT in the past among some South Africans has been ascribed to alcoholic beverages with high iron content (117). It is possible that estrogen treatment and hepatotropic viruses associated with PCT onset also influence iron homeostasis (28, 41, 117). Many experiments have demonstrated that iron stores also play an important role in the inhibition of UROD and subsequent uroporphyria in rodents. In rats, the rate of development of porphyria caused by HCB is influenced by sexual dimorphism of hepatic iron levels (103) and stimulated by injections of iron (122-126). Conversely, it is retarded by bleeding or administration of an iron chelator (127, 128). Similarly, lowering hepatic iron levels by phlebotomy, an orally active iron chelator, or diets deficient in iron protects mice from the uroporphyrogenic properties of TCDD or PCBs and modulates other aspects of liver toxicity (107, 129-132). In contrast, administration of iron to C57BL mice markedly enhances general hepatic toxicity and porphyria induced by these chemicals (112, 133, 134). Most remarkably, pretreatment of C57BL/10ScSn mice with iron dextran greatly sensitizes them both to the uroporphyria induced by HCB and to hepatocellular cancer (109, 135-138). Although excretory routes of HCB metabolites are altered, overall metabolism is not appreciatively changed (139). UROD activity is decreased (sometimes to 6 months as the hepatic iron levels became elevated (150). Thus, clearly iron metabolism seems to play a pivotal role in uroporphyria. Although a threshold of iron is required for porphyria development in PCT and experimental models, the mechanisms by which iron is mobilized and acts is a separate issue and is discussed in section 7.

6. Genetic Complexity 6.1. Genetic Factors in Humans. Several genetic factors are involved in the pathogenesis of hepatic uroporphyria in humans (Table 1). Mutations in the UROD and HFE genes are strongly associated with PCT and have been shown to be importantfactorsindeterminingsusceptibilitytoPCT(41,151,152). Inherited deficiency of UROD is the strongest factor predisposing to the development of PCT that has been identified to date (see section 3). In populations of northern European descent, about 20% of patients are homozygous for the C282Y mutation in the hemochromatosis gene, HFE, that is involved in the regulation of iron absorption (151-153). Patients with the inherited iron storage disorder, hemochromatosis, have the same genotype, but in PCT, the increase in hepatic iron concentrations is usually less than that in clinically overt hemochromatosis. In other populations, where the C282Y allele is less common, the frequency of the H63D variant, which also influences body iron stores but to a lesser extent (154), may be increased in PCT (41). However, in many PCT patients iron stores are increased without mutations in the HFE gene. Hepatic hepcidin expression is down-regulated in many PCT patients, irrespective of HFE genotype, and variants in genes modulating its operation may also contribute to hepatic siderosis in this condition (155). Although UROD mutations and homozygosity for the C282Y HFE mutation act individually as risk factors for PCT, neither appears sufficient by itself to produce PCT, at least in the great majority of cases. Interaction with other acquired and genetic factors appears to be required (41). Unknown genetic factors have also been postulated as an explanation for the difference in susceptibility noted between individuals and families receiving similar diets during the outbreak of HCB uroporphyria in Turkey (156). 6.2. Genetic Variation in Experimental Uroporphyria. Studies in strains of rodents have been one approach to exploring the role of the genetic background in determining susceptibility to develop uroporphyria in response to chemical and other

acquired factors (157). The marked depression of UROD activity and porphyria induced by TCDD differs greatly between strains of mice (106, 110, 133). C57BL/6J and C57BL/10ScSn mouse strains are particularly susceptible, whereas DBA/2 mice are highly resistant, even at much higher doses (106). Initially, crosses of these strains suggested that the difference between C57BL/6J and DBA/2 strains was solely dependent on the inheritance of a responsive allele of the Ahr gene (111). C57BL/ 6J and C57BL/10ScSn mice possess an AHR (Ahrb1 allele) which binds TCDD with high affinity, whereas DBA/2 mice possess a low affinity AHR (Ahrd allele). Subsequent investigations of the porphyric response (and hepatic toxicity) to TCDD of other strains and interstrain crosses have shown a much more complicated pattern involving polymorphisms of genes in addition to Ahr (133, 158, 159). Importantly, some other Ahrd strains, such as AKR and SWR, and some strains of Ahrb mice, such as BALB/c mice which are resistant, become susceptible to uroporphyria, overcoming resistance, if administered iron in combination with TCDD. In contrast, DBA/2 mice remain insensitive (133, 134). Thus, although the AHR can be a dominant requirement and the Ahrb1 allele an important susceptibility factor for TCDD hepatotoxicity in mice, other genes play a significant role and probably include polymorphisms of those whose functions have not yet been clarified (112, 160) (Table 1). Some of these may be important in iron homeostasis. The sensitivity of 129S6/SvEvTAC mice to alcohol is greatly increased by the presence of the Hfe-/- null gene, causing deposition of iron, but C57BL/6J mice with the same null gene inserted are resistant (161). The sensitivities of inbred strains of mice to uroporphyria induced by iron alone do not correlate with the Ahr genotype, despite the fact that DBA/2 mice remain the most insensitive, whereas an outbred strain gives a range of responses compatible with a variety of genetic factors being involved (145). Like familial PCT patients who show half normal UROD activity, mice heterozygous for the Urod null gene do not develop uroporphyria unless another factor is present such as administration of iron and ALA or hepatic iron overload produced by crossing with Hfe null mice (148, 162). In conclusion, the induction of uroporphyria in in-bred lines of mice is a complex genetic trait. This means that methods of genetic dissection and quantitation should, ultimately, shed light on the mechanisms and susceptibility genes underlying sporadic PCT. 6.3. Search for Susceptibility Genes in Mice. As a first step to explore this complexity in mice, quantitative trait locus (QTL) analysis with polymorphic DNA markers has been employed to associate chromosomal loci (positions of susceptibility genes) with propensity for the uroporphyric response (163). Susceptibility loci (QTL) for porphyria induced by TCDD and HCB were identified in iron loaded F2 crosses between susceptible strains and the resistant line DBA/2 (Table 2). With either C57BL/6J or C57BL/10ScSn as the sensitive strain, a QTL on chromosome 12 corresponded in position to the Ahrb 1 allele as anticipated. This was not observed with an intercross between DBA/2 and the Ahrd strain SWR which is susceptible to TCDD (160, 164). In addition, compared to DBA/2, both C57BL/6J and SWR mice possessed at least one susceptibility gene to TCDD on chromosome 11. A QTL on chromosome 11 was not detected with HCB in C57BL/10ScSn mice, but QTLs on chromosomes 14 and 17 were found (164). A QTL at a similar position on chromosome 14 was also detected in the susceptibility of C57BL/6J mice to TCDD but not with SWR. More than one susceptibility gene on chromosome 1 appeared to contribute

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Table 2. Significant Susceptibility Loci Observed for Chemical-Induced Porphyria in Mice susceptible strain

Ahr allelea

agent

chromosomeb

C57BL/10ScSn C57BL/6J SWR

b1 b1 d

HCB TCDD TCDD

12,14,17 11,12,14 1,9,11

a Ahrb1 and Ahrd alleles on chromosome 12 code for high and low affinity AHRs binding TCDD, respectively. b Loci were derived by QTL analysis of F2 crosses between susceptible strains and the resistant DBA/ 2 strain. Some loci probably represent a composite of susceptibility genes (160). All mice received a single s.c. dose of iron (800 mg/kg body weight) prior to chemical treatment (HCB 200 ppm in the diet; TCDD 75 µg/kg body weight) (160, 164).

to the sensitivity of the iron loaded SWR strain to TCDD (160). Apart from the Ahr gene, most loci do not correspond to regions containing genes that are already known to be implicated in uroporphyria development or iron metabolism. Further studies are required for their identification. A similar approach to find loci and eventually genes contributing to susceptibility to uroporphyria caused by iron treatment alone and a comparison with those demonstrated for TCDD and HCB could be useful steps in understanding the contribution of various genes in PCT and provide further links between PCT and the experimental models in understanding the mechanisms. Studies of this kind would also be of importance as an example of determining susceptibility to the toxic action of other chemicals. 6.4. Overview. Although the porphyria phenotype is similar in these mouse models of PCT and the human disorder (Figure 3), polymorphisms in genes affording susceptibility vary markedly in their identity and penetrance depending on the background strain, i.e., individual genetic makeup, and on the chemical agent. Alleles of the Ahr may play an important role in some mouse models (112, 160), but expressions of other genes have a significant modulating influence. Importantly, although knockout of the genes for CYP1A2 and possibly that for CYP1A1, which are regulated by the AHR, have a marked influence on uroporphyria development in mice (113-115, 165, 166), their downstream expression and enzyme activities do not always correlate with the porphyric response (160, 164, 167). So far, no linkage of human AHR polymorphisms with susceptibility for PCT has been reported, and association between variants of the CYP1A2 gene and PCT has been equivocal (55, 168). This confirms that studies with knockout strains, although valuable mechanistically, should not be assumed as demonstrating susceptibility genes in mice or in patients.

7. Consequence of Gene-Chemical Interaction Clearly, there is a great deal of evidence showing that the development of PCT in humans and the uroporphyria caused by chemicals in experimental animals and people are complex interactions in terms of triggering agents and genetic susceptibility (Figure 4) in which iron homeostasis plays a major role. Some susceptibility genes may be associated with a wide range of triggering agents, and others may be specific to a particular one. Genes highly pertinent to alcohol, as in its metabolism, or to hepatotropic viruses may be far less influential in uroporphyria caused by TCCD in which polymorphisms in the AHR gene might be expected to predominate. Even so, it is likely that there are common metabolic pathways that can be influenced by the interaction of the chemical and genetic factors in these interactions. What might be the consequence of such interaction?

Figure 4. Scheme showing complex interactions between genetic factors, chemicals, drugs, and endogenous factors, including iron homeostasis, causing uroporphyria. Uroporphomethene (A), the first product in the oxidation of uroporphyrinogen to uroporphyrin, is an inhibitor of UROD and has been isolated from a porphyric liver (174). The oxidation process, by an unknown route, also leads to other products such as hydroxyspirolactone- (B) and dihydroxy-urochlorins (C), which have unknown biological consequences (179).

It now seems probable that an oxidative process is the ultimate mechanism for UROD inhibition or inactivation, which entails catalysis by iron as a consequence of specific processes of Fe2+ mobilization (41, 67, 68, 134, 141, 169). A number of studies in PCT patients and with experimental models have demonstrated that the decrease in the catalytic activity of UROD is not accompanied by a loss of enzyme protein (170-172). Uroporphomethene, an initial oxidation product of uroporphyrinogen in which one methane bridge is oxidized (173) (Figure 4), has been isolated from porphyric tissue (174) and accounts, in part, for the inhibitory factors toward UROD that have been reported previously (108, 175, 176). Whether further ring and side chain oxidation products of uroporphyrinogen or their precursors (177, 178), which have been identified in porphyric liver (Figure 4) (179), also have a role and whether simple inhibition of UROD is sufficient to account for the persistence of the porphyric response remain to be determined (180). These products derived from uroporphyrinogen are themselves markers of an oxidation process occurring. Chemically, Fe2+ is a powerful catalyst of uroporphyrinogen oxidation to yield uroporphyrin and other products, but the metabolic route and how such a process occurs to yield an inhibitor and depression of UROD activity causing PCT and other uroporphyrias, specifically under certain conditions, are a puzzle (176, 181). Uroporphyria is not usually a characteristic of iron overload. Because it is highly toxic, little free Fe2+ usually exists within a cell; its release to oxidize uroporphyrinogen (141) would have to be the consequence of a specific process or circumstance dictated by the synergism of the genetic and chemical factors and at the right intracellular and molecular site. The genetically variable powerful effect of TCDD and HCB in animals demonstrate that polymorphisms of genes associated with xenobiotic responses could play a significant role, as exemplified by the Cyp1a2 and Ahr knockout mouse lines (112), as could

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the supply of heme precursors to give a large pool of oxidizable uroporphyrinogen (143, 146, 147) and antioxidant status (182). However, this can also occur in the absence of additional iron. Oxidation of uroporphyrinogen (or its precursor 1-hydroxymethylbilane) by a microsomal system is an attractive hypothesis, apparently supported by the Cyp1a2 knockout studies (165). Alternatively, perhaps the CYP is involved in releasing toxic iron in the vicinity of uroporphyrinogen (176, 183).

8. Conclusions Simple interactions between single gene polymorphisms and chemical or drug exposure are likely to contribute to the minority of toxic responses. As with many clinical disorders, many toxicological disorders are probably the consequence of multiple interactions between a number of gene variants and triggering agents but resulting in a common phenotype. Genetic factors can be crucially important but may not be overtly obvious from association studies because of their complexity, their variability of penetrance, and a variety of triggering agents and environments. The comparison of the chemical and genetic factors that can contribute to experimental uroporphyria in laboratory animals and those known to be associated with the onset of the disease PCT in patients is a good paradigm of the complexity that may underlie an apparently simple toxic phenotype. Methodical genetic and molecular approaches, similar to those used for exploring uroporphyria in PCT patients and in laboratory animals, should eventually lead to quantitation and mechanistic understanding of other complex gene-chemical interactions which occur in the toxicities of drugs and chemicals in the liver. Acknowledgment. We thank the anonymous reviewers for their constructive comments and regret that many papers could not be included for the sake of brevity.

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