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Differences in Toxicological and Pharmacological Responses Mediated by Polymorphic Cytochromes P450 and Related DrugMetabolizing Enzymes Hiroshi Yamazaki* Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, 3-3165 Higashi-tamagawa Gakuen, Machida, Tokyo 194-8543, Japan ABSTRACT: Research over the past 30 years has elucidated the roles of polymorphic human liver cytochrome P450 (P450) enzymes associated with toxicological and/or pharmacological actions. Thalidomide exerts its various pharmacological and toxic actions in primates through multiple mechanisms, including nonspecific modification of many protein networks after bioactivation by autoinduced human P450 enzymes. To overcome species differences between rodents, currently, nonhuman primates and/or mouse models with transplanted human hepatocytes are used. Interindividual variability of P450-dependent drug clearances in cynomolgus monkeys and common marmosets is partly accounted for by polymorphic P450 variants and/or aging, just as it is in humans with increased prevalence of polypharmacy. Genotyping of P450 genes in nonhuman primates would be beneficial before and/or after drug metabolism and toxicity testing and evaluation as well in humans. Genome-wide association studies in humans have been rapidly advanced; however, unique whole-gene deletion of P450 2A6 was subsequently developed to cover nicotine-related lung cancer risk study. Regarding polypharmacy, toxicological research should generally be aimed at identifying the risk of adverse drug events following specific potential drug exposures by examining single or multiple metabolic pathways involving single or multiple drug-metabolizing enzymes. Current and next-generation research of drug metabolism and disposition resulting in drug toxicity would be addressed under advanced knowledge of polymorphic and age-related intra- and/or interspecies differences of drug-metabolizing enzymes. In the near future, humanized animal models combining transplanted hepatocytes and a humanized immune system may be available to study human immune reactions caused by human-type drug metabolites. Such sophisticated models should provide preclinical predictions of human drug metabolism and potential toxicity.

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CONTENTS

1. Introduction 2. Species Differences between Experimental Animals (Including Nonhuman Primates) and Humans in Metabolic Activation and Deactivation 3. Genetic Polymorphism of P450 2A6 Is Associated with Nicotine-Related Cancer Risk 4. Assessment of Polypharmacy and Drug Interactions in the Clinical Setting 5. Metabolic Activation and Detoxification of Reactive Intermediates Formed through Oxidation of Drugs in Humanized-Liver Mice 6. Conclusions and Future Perspectives Author Information Corresponding Author Funding Notes Biography Acknowledgments Abbreviations References

© XXXX American Chemical Society

1. INTRODUCTION I congratulate all those associated with Chemical Research in Toxicology on its 30th anniversary. In my 2008 editorial article,1 I stated that “Chemical Research in Toxicology is an excellent forum for reporting and discussing a variety of such toxicological studies as it endeavors to bring some new energy to the field.” Since then, that energy has resulted in new developments and exciting breakthroughs in this important field. Toxicology research is broad in scope and offers numerous exciting research opportunities. Such opportunities are typically characterized by a global bipolarization between large projects carried out by national research institutes/ consortia and safety evaluations of typical known chemicals or new drug candidates in individual laboratories. This perspective focuses on the mechanistic evaluation of reactive metabolites mediated by polymorphic cytochromes P450 and related drugmetabolizing enzymes and their potential toxicity risk.

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Special Issue: CRT30 Received: August 23, 2016 Published: October 17, 2016 A

DOI: 10.1021/acs.chemrestox.6b00286 Chem. Res. Toxicol. XXXX, XXX, XXX−XXX

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In a definitive pharmacokinetic study in humans,6 the effectiveness was established of caffeine, S-warfarin, omeprazole, metoprolol, and midazolam (in combination) as probe substrates of human P450s 1A2, 2C9, 2C19, 2D6, and 3A, respectively. The results of the human P450 cocktail probe of metabolic clearances previously described6 were compared with those of the same cassette dosing in cynomolgus monkeys (Macaca fascicularis, an Old World primate),7 common marmosets (Callithrix jacchus, a New World primate),8 and humanized-liver mice.9 To evaluate species differences in drug metabolism, in humanized-liver mice, the liver has been partially destroyed and then repopulated to a degree of at least 70% with human hepatocytes in the thymidine kinase transgene nonobese diabetes-severe combined immunodeficiency-interleukin-2 receptor gamma chain-deficient (TKNOG).9 On the basis of the measured pharmacokinetics in cynomolgus monkeys and common marmosets, simplified human physiologically based pharmacokinetic (PBPK) models for the probe substrates9,10 could successfully estimate the corresponding human pharmacokinetics using in vitro metabolic clearance data. It should be noted that, to overcome the limited availability of human hepatocytes, the human hepatic cell line HepaRG was evaluated, with promising results, as a source of donor cells for liver reconstitution in the humanizedliver mouse model.11 The utility of such simplified PBPK models established with data from nonhuman primate animal and humanized mice models could be extended to toxicologists for the investigation of a variety of chemical species. Recently, a human hepatocyte replacement index for TK-NOG mice was proposed to help extrapolate important pharmacokinetic parameters using a virtual chimeric mouse with 100% humanized liver.12 This unique method utilizing humanizedliver mice in vivo succeeded in a case study in predicting in humans the disproportionate metabolite formation of a partial glucokinase activator (codename PF-04937319),12 which could not have been reliably predicted from in vitro previous metabolism studies during preclinical investigations. Individual differences in humans in terms of drug metabolism may be caused predominantly by whole-gene deletion or impaired variants of P450s.13 In general, cynomolgus monkey and common marmoset P450 enzymes show high sequence homology to their human counterparts.14 Genetic polymorphisms similar to those in humans have recently been found in cynomolgus monkey and marmoset P450 2C19.15−19 However, a variety of cynomolgus monkey and common marmoset P450 2C variants that do not completely match the corresponding human P450 variants have been extensively reported.20 Fast eliminations of P450 2D-dependent metoprolol and P450 3A-dependent midazolam in limited numbers of cynomolgus monkeys7 and common marmosets8 have been documented. The understanding of polymorphic nonhuman primate P450 variants (especially P450 2D/3A variants that can lead to adverse drug reactions) is clearly important for successfully using these animal models during drug development. To apply the principles of reduction, refinement, and replacement (the 3Rs) in the use of laboratory animals, the timing of the genotyping of nonhuman primates used in research and toxicity testing will become similar to that in humans.

Previous large toxicological research projects were conducted using experimental animals such as rodents. However, human biomonitoring evaluates chemical concentrations in biological specimens (as a result of absorption, distribution, metabolism, and excretion) rather than estimating intake doses, as evaluated in animal studies. To overcome the problems associated with species differences in drug-metabolizing enzymes, the highsensitivity screening of chemicals within human blood and urine media was recently proposed. The important polymorphic P450s regarding drug metabolism and toxicity in individuals are in the P450 2C or 2D families. The development of rapid genotyping methods for human drugmetabolizing enzymes (e.g., the typical nicotine metabolizing P450 2A6, the genotyping of which was excluded in early genome-wide association studies) is also important for clinical research. Additionally, the mode of action of chemicals retained in tissue after metabolism and elimination should be considered for potential toxicity risk. Extensive research regarding the formation of human-specific drug metabolites is conducted in many pharmaceutical laboratories following U.S. Food and Drug Administration guidelines on safety testing of drug metabolites. However, because of their proprietary nature, the results for new drug candidates are not publicly available and are not generally presented at conferences or made available in journals or databases. Investigation of the possible formation of reactive metabolites as part of the metabolic clearance of potential drug candidates and the identification of simple and reliable biomarkers are important. These are currently hot topics in evaluation of the toxicological potential of new drug candidates. To predict the generation of highly reactive metabolites, a combination of time-dependent inhibition and glutathione trapping assays has been proposed.2 In terms of biomarkers, the plasma mRNA levels of liver-specific albumin and apolipoprotein H3,4 are reportedly increased in rats and patients with liver injury, and these biomarker levels correlated with elevated serum alanine aminotransferase levels. These mRNAs were also found to be increased in plasma after the administration of solutions of anticancer agents during transcatheter arterial chemoembolization, which induces specific injury to the liver.4 The human liver microsomal P450 enzymes have been identified to be associated with toxicological and/or pharmacological actions. Currently, nonhuman primates and/or humanized-liver mice are successfully used as preclinical drug metabolism models to identify disproportionate metabolite formation and nonspecific protein bindings in humans, thereby indicating potential toxicity in humans. Interindividual variability of P450-dependent drug clearances or drug activation/deactivation in cynomolgus monkeys and common marmosets is partly accounted for by polymorphic P450 enzymes and/or aging, just as it is in humans. Progress in current and next-generation research requires intra- and/or interspecies differences of drug metabolism and disposition resulting in drug toxicity to be addressed in detail for mechanistic evaluation of reactive metabolites.

2. SPECIES DIFFERENCES BETWEEN EXPERIMENTAL ANIMALS (INCLUDING NONHUMAN PRIMATES) AND HUMANS IN METABOLIC ACTIVATION AND DEACTIVATION Drug metabolizing forms of polymorphic P450 mediate oxidative clearances of a variety of compounds in humans.5 B



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3. GENETIC POLYMORPHISM OF P450 2A6 IS ASSOCIATED WITH NICOTINE-RELATED CANCER RISK Nicotine dependence, smoking behavior, and the risk of chronic obstructive pulmonary diseases and lung cancer show extensive linkage to genetic polymorphism in nicotinemetabolizing enzymes,21 especially P450 2A6.22 Predicted P450 2A6 phenotypes based on P450 2A6 genotypes were found to be determinants of smoking behavior and tobaccorelated lung cancer risk (Figure 1),23 particularly for squamous

plasma than is nicotine, can promote lung tumorigenesis via suppression of apoptosis, giving more support to the impacts of genetic polymorphism of P450 2A6 on tobacco-related lung cancer risk.37 To help prevent tobacco-related diseases and to identify those at high risk, a simple and reliable detection method of P450 2A6 genotypes is needed to support individual counseling. The novel mechanism of lung tumor promotion mediated by cotinine37 emphasizes the importance of P450 2A6 as a molecular target for the chemoprevention of tobaccorelated cancers. An important deleterious effect of smoking on clinical outcomes of low-dose aspirin treatments for preventing colorectal tumor recurrence in Asian patients has been noted.38 Subjects treated with aspirin had reduced colorectal tumorigenesis with an adjusted odds ratio of 0.60 (95% confidence interval 0.36−0.98); however, smokers treated with aspirin had a significantly increased risk with an odds ratio of 3.44.38 Individual differences in the clinical response to aspirin may be associated with smoking. In future large research projects, the genotyping of polymorphic P450 2A6 might act as a biomarker for the preventive effects of low-dose enteric-coated aspirin tablets for chemoprevention of colorectal tumors.

Figure 1. Causal model in smokers genotyped for P450 2A6. Tobacco smokers with high- or low-activity P450 2A6 mutations adjust their smoking intensity to maintain plasma levels of nicotine. If nicotine is cleared rapidly from the body, more extensive smoking habits often result. Extensive smoking results in exposure to tobacco-related Nnitrosamines activated by P450 2A6 (leading to the initiation of DNA damege) and accumulation of cotinine produced by P450 2A6 (leading to the inhibition of cell apoptosis), and elevated promotion likely results in a high lung cancer risk.

4. ASSESSMENT OF POLYPHARMACY AND DRUG INTERACTIONS IN THE CLINICAL SETTING Aging is one of many important determinant factors for interindividual differences in pharmacokinetics and drug responses (pharmacodynamics) that may cause adverse drug reactions. In 2008, analysis of a cohort of 3005 US communitydwelling older adults found that prescription medications, nonprescription medications, and supplements were commonly used together, with nearly 1 in 25 individuals potentially at risk for a major drug interaction.39 Recently, drug interactions have been reported among elderly patients,40 and even among pediatric patients,41 in which polypharmacy was a factor. Many patients are likely to be exposed to substantial polypharmacy and potential drug interactions. Future research should generally be aimed at identifying the risk of adverse drug events following specific potential drug exposures by examining single or multiple metabolic pathways involving single or multiple drug-metabolizing enzymes. As part of risk analysis regarding polypharmacy in psychiatry, plasma concentrations of antipsychotic olanzapine were determined in 14 male and 7 female Japanese patients (including 6 smokers) ranging in age from 32 to 69 years (mean, 50 years). The results showed that olanzapine clearance was not affected by P450 2D6 or f lavin-containing monooxygenase 3 genotypes, smoking behavior, or the number of coadministered drugs as a single factor because olanzapine clearance is mediated by multiple enzymes involved in two major pathways and one minor pathway.42 Similarly, plasma concentrations of the antipsychotic drug risperidone and its pharmacologically active metabolite 9-hydroxyrisperidone (paliperidone) were measured in 15 male and 12 female Japanese clinical patients ranging in age from 24 to 75 years (mean, 52 years). Individual differences in metabolic clearances of risperidone were not significantly influenced by the genotypes of P450 2D6/3A5 or by the number of coadministered P450 2D6 inhibitor drugs as a single determinant factor.43 In contrast, the trough plasma concentration/dose ratios of second-generation psychiatric drug mirtazapine in 1 male and 13 female Japanese patients (including 2 smokers) ranging in age from 26 to 96 years

cell and small cell carcinoma, which are highly associated with cigarette smoking24 in male Japanese heavy smokers.25,26 Several reports from genome-wide association studies focusing on lung cancer risk in different ethnic populations have suggested a variety of susceptibility genes, such as telomerase reverse transcriptase,27−29 tumor protein p63,29,30 alcohol dehydrogenase 1C, and aldehyde dehydrogenase 2.31 Because P450 2A6 genotyping was not included in early genome-wide association studies, unique genotyping primers32 for wild-type and whole-gene deletion of P450 2A6 for traditional polymerase chain reaction (PCR)/restriction fragment length polymorphism analysis33 and for multiplex real-time PCR with duallabeled probes were subsequently developed. These developments have facilitated the genotyping of wild-type (2A6*1/*1), whole-gene deletion (2A6*4/*4), and their heterozygote (2A6*1/*4) using blood samples.34 One application of precise analytical software to genome-wide association studies for the determination of P450 2A6 haplotypes has been reported. This study included copy number and single nucleotide polymorphisms in the P450 2A6 locus and could distinguish P450s 2A7 and 2A13.30 Recently, the effects of P450 2A6 variants on lung cancer risk were analyzed using the Transdisciplinary Research in Cancer of the Lung consortium genome-wide association studies data set.35 Moreover, population-specific variation in P450 2A6 genes has reportedly contributed to genome-wide association of the laboratory-based nicotine metabolite ratio.36 These reported findings collectively support the long-standing hypothesis that faster P450 2A6 metabolic capacity causes smokers to smoke more extensively and to be exposed to higher levels of tobacco-related N-nitrosamines. These N-nitrosamines are then metabolically activated to reactive metabolites (also by P450 2A6), resulting in an increased risk for lung cancer (Figure 1). Furthermore, nicotine metabolite cotinine, which is more slowly cleared from human C



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zone51−53 were causal factors of the toxicity in these patients,50 in which null allele frequencies for GSTM1 and GSTT1 are 50% and 50%, respectively, in a Japanese population. Reproducing the human teratogenicity of thalidomide in mouse and rat models was previously unsuccessful. However, in 2016, an in vitro whole-embryo culture system of embryos taken from transchromosomic mice containing a human P450 3A cluster54 showed some limb abnormalities with thalidomide.55 Thalidomide and its disproportionate human metabolite 5-hydroxythalidomide are oxidized by autoinduced human P450 3A enzymes56 to reactive metabolite(s) that are trapped as glutathione conjugates57,58 in humanized-liver mice.59 Using modified chemical probes in conjunction with ferric beads, the protein cereblon was found to be a primary teratogenic target of thalidomide, lenalidomide, and pomalidomide.60,61 Intravenously administered 5-hydroxythalidomide is further bioactivated by human P450 3A enzymes in vivo and trapped with nonspecific proteins in humanized mouse models with human P450 3A or hepatocytes.62 By two-dimensional electrophoresis/ accelerator mass spectrometry,63,64 a zone analysis of proteins binding radiolabeled troglitazone and flutamide found a few proteins with high covalent binding content and high target protein concentration.62 Although the target proteins quoted above with the highest covalent binding levels were different for hepatotoxic troglitazone and flutamide,64 it has been reported that selenium binding protein 1 (acetaminophen binding protein), suggested to be a kind of common target in previous studies with troglitazone and 5-n-butyl-pyrazolo[1,5-a]pyrimidine,63,64 was not detected in a recent study of radiolabeled 5-hydroxythalidomide.61 GSTA1 has been ranked as a minor target binding protein with trogltazone.63,64 GSTA1 appears to be an important enzyme trapping activated 5hydroxythalidomide in humanized mouse models. Cereblon was not thrown into the limelight in the metabolic activation of radiolabeled 5-hydroxythalidomide by human P450 enzymes in two-dimensional electrophoresis/accelerator mass spectrometry.62 Thalidomide clearly exerts its various pharmacological and toxic actions through multiple mechanisms, including nonspecific modification of many protein networks after bioactivation by human P450 enzymes. A recent summary of different humanized animal systems is published in this journal as a part of a special issue.65 Considering the clinical potential of thalidomide, the mechanisms by which it exerts its potential negative effects require further evaluation. These mechanisms include the possibilities of drug interactions, especially autoinduction, during thalidomide therapy and the roles of reactive metabolites59 in the efficacy and side effects of thalidomide in humans. Two new potentially teratogenic thalidomide-related drugs, pomalidomide and lenalidomide, are pthalidimide ringhydroxylated.66,67 They lack P450 induction potential or exhibit no metabolism68 with P450 3A induction, leading to reduced toxicity and increased potency, respectively. A future strategic pathway toward the development of new anticancer drugs should include screening for thalidomide-related analogues that do not result in undesired metabolic bioactivation but have good immunomodulatory properties.

(mean, 73 years) were variously influenced by the P450 2D6 and P450 3A5 genotypes and coadministered drugs.44 There are a myriad possible drug combinations with increasing coadministrations, but it may be worth understanding that drugs metabolized by multiple pathways involving multiple drug-metabolizing enzymes are less likely to be involved with excessive drug exposure as a result of drug interactions than drugs metabolized in a single pathway mediated by a single enzyme susceptible to genetic polymorphism, even under these limited numbers of studies. To improve drug safety in high-risk populations, appropriate prescribing assessment by toxicologists will become increasingly important. Age-related changes in pharmacokinetics have been well summarized in humans.45−47 To reduce the related risks, it is important to predict how the toxicokinetics or pharmacokinetics of drug candidates will change in older patients. Agerelated changes in physiological parameters and reduced hepatic clearances of some human P450 2C19 and 3A substrates in cynomolgus monkeys are in agreement with those reported in humans.7,20,48 Consequently, aged cynomolgus monkeys may be suitable models for predicting such agerelated changes of pharmacokinetics and physiological parameters in humans. Age-related pharmacokinetic changes in other nonhuman primate animal models would likely bring to light important safety aspects of drugs developed primarily for elderly patients. In the future, developing pharmacokinetic models for predicting drug concentrations in pediatric patients will be another challenge for research with nonhuman primates. The utility of nonhuman primates and/or humanized-liver mice to predict human toxicity is highlighted in in vivo systems as mentioned above. On the other hand, recent progress in vitro systems should be also noted regarding advanced human hepatic cell culture models, such as three-dimensional cultures and/or cocultures,11 which open the possibility to perform chronic toxicity or drug interaction tests in a human setting. A variety of three-dimensional culture systems for hepatic cells derived from humans have been found to substantially increase the predictability of hepatotoxicity over conventional twodementional systems. For a simple example, catalytic function and/or induction of human P450 1A2, 2B6, and 3A4 can be readily assessed with human HepaRG cells cultured in threedimensional cultures in medium drops prepared with hangingdrop plates.49 Furthermore, there could be perspective challenges for the investigation of age related effects that could be mimicked in in vitro systems using hepatocytes from human donor sources across a variety of ages in a battery of aged nonhuman primates in vivo.

5. METABOLIC ACTIVATION AND DETOXIFICATION OF REACTIVE INTERMEDIATES FORMED THROUGH OXIDATION OF DRUGS IN HUMANIZED-LIVER MICE Regarding the formation of human-specific drug metabolites, troglitazone50 is an example of a drug that was launched on the market and then subsequently withdrawn in the U.K., U.S., and Japan as a result of idiosyncratic liver toxicity. Among the 25 case patients in Japan who suffered troglitazone-induced liver injury and 85 controls, a strong correlation with transaminase elevations has been observed in the combined glutathione Stransferase (GST) M1 and GSTT1 null genotype (odds ratio, 3.69; p < 0.01).50 It is possible that increased exposures to P450 3A4-mediated reactive epoxide metabolites from troglita-

6. CONCLUSIONS AND FUTURE PERSPECTIVES Reactive metabolite studies constitute an important area of research for clinical, industrial, and academic toxicologists. Evaluation of reactive metabolites derived from drugs is important prior to new drug approval as well as during the D



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Biography

postmarketing period. To develop new medicines and utilize them effectively, epidemiological and mechanistic studies of drugs and drug candidates will further reveal the importance of genetic polymorphisms of drug-metabolizing enzymes and will make great contributions to the field of toxicology. miR-122, a completely conserved liver-specific miRNA, has shown great potential as a diagnosis of drug-induced liver injury biomarker.69 The mechanistic evaluation of reactive metabolites and their potential for predicting individual risk and related biomarker research will long remain a dynamic and challenging aspect of toxicology. Collaborations and combinations of new techniques are important in many research areas. Studies of drug metabolism using nonhuman primate animal models or humanized-liver mice may be useful in evaluating drug metabolism, disposition, and potential toxicity in humans. Transplantation of human hepatic cell line HepaRG cells has been reported to yield hepatocyte-like colonies in live mice, in a way similar to that of primary human hepatocytes in humanized liver TK-NOG mice,11,70 suggesting a possible human cell source for the steady generation of humanized mouse models in the future. Genotyping of P450 genes associated with drug-metabolizing enzymes in nonhuman primates would be beneficial before and/or after drug metabolism research and toxicity testing in such primates. The toxicity of drugs has extensively been studied in terms of metabolic activation of the parent drug over the past 30 years; however, other factors such as a humanized immune response systems should be included for mechanistic evaluation of some reactive metabolites. For this reason, humanized mice with reconstituted human immune systems are also essential to study human immune reactions in vivo and are expected to be useful for studying human allergies. A novel transgenic NOG mouse strain bearing human interleukin-3 and granulocyte macrophage colony-stimulating factor genes has been recently developed.71 Mouse models combining transplanted human hepatocytes and a humanized immune system may become available in the near future to study human-type drug metabolite identification and resulting human immune reactions. Application of these humanized models and/or nonhuman primates, coupled with mass spectrometry methods, will hopefully provide accurate preclinical predictions of human drug metabolism and potential toxicity.

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Dr. Hiroshi Yamazaki has been Professor at Showa Pharmaceutical University, Tokyo, since 2005. He received his Ph.D. in Pharmaceutical Sciences from Osaka University and trained as a postdoctoral fellow at Vanderbilt University in 1994. He was a scientist at Osaka Prefectural Institute of Public Health (1987−1998) and Associate Professor of Kanazawa University (1998−2001) and Hokkaido University (2001−2005). His research focuses on polymorphic cytochromes P450 and flavin-containing monooxygenases, and he has authored more than 350 publications. He is an EAB member of Chemical Research in Toxicology, a Japanese Society for the Study of Xenobiotics (JSSX) fellow, and a recipient of the JSSX Award.

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ACKNOWLEDGMENTS I thank Professors Norio Shibata and F. Peter Guengerich and Drs. Hiroshi Suemizu, Erika Sasaki, Yasuhiro Uno, Shotaro Uehara, Makiko Shimizu, and Norie Murayama for their support.

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ABBREVIATIONS

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REFERENCES

GST, glutathione S-transferase; NOG mice, nonobese diabetessevere combined immunodeficiency-interleukin-2 receptor gamma chain-deficient mice; P450, general term for cytochrome P450 enzymes (EC 1.14.14.1); PBPK modeling, physiologically based pharmacokinetic modeling; PCR, polymerase chain reaction

(1) Yamazaki, H. (2008) Individual differences in toxicological response caused by a diversity of chemicals: Observations in Japan. Chem. Res. Toxicol. 21, 3−4. (2) Nakayama, S., Takakusa, H., Watanabe, A., Miyaji, Y., Suzuki, W., Sugiyama, D., Shiosakai, K., Honda, K., Okudaira, N., Izumi, T., and Okazaki, O. (2011) Combination of GSH trapping and timedependent inhibition assays as a predictive method of drugs generating highly reactive metabolites. Drug Metab. Dispos. 39, 1247−1254. (3) Okubo, S., Miyamoto, M., Takami, K., Kanki, M., Ono, A., Nakatsu, N., Yamada, H., Ohno, Y., and Urushidani, T. (2013) Identification of novel liver-specific mRNAs in plasma for biomarkers of drug-induced liver injury and quantitative evaluation in rats treated with various hepatotoxic compounds. Toxicol. Sci. 132, 21−31. (4) Okubo, S., Miyamoto, M., Ito, D., Takami, K., and Ashida, K. (2016) Albumin and apolipoprotein H mRNAs in human plasma as potential clinical biomarkers of liver injury: analyses of plasma liverspecific mRNAs in patients with liver injury. Biomarkers 21, 353−362. (5) Rendic, S., and Guengerich, F. P. (2012) Contributions of human enzymes in carcinogen metabolism. Chem. Res. Toxicol. 25, 1316− 1383.

AUTHOR INFORMATION

Corresponding Author

*Tel: +81-42-721-1406. Fax: +81-42-721-1406. E-mail: [email protected]. Funding

This work was supported in part by the Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research 26460206 and the Ministry of Education, Science, Sports and Culture of Japan (MEXT)-supported Program for the Strategic Research Foundation at Private Universities, 2013−2018. Notes

The author declares no competing financial interest. E



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