Role of Mixed-Function Oxidases in Insect Growth and Development

10

Downloaded by UNIV OF MASSACHUSETTS AMHERST on October 24, 2017 | http://pubs.acs.org Publication Date: April 26, 1985 | doi: 10.1021/bk-1985-0276.ch010

Role of Mixed-Function Oxidases in Insect Growth and Development C . F. W I L K I N S O N Department of Entomology, Cornell University, Ithaca, NY 14853

In addition to their well established role in catalyzing the metabolism of a wide variety of naturally occurring and synthetic xenobiotics, cytochrome P-450mediated mixed-function oxidases are of critical importance in the biosynthesis and regulation of the major hormones (ecdysteroids and juvenile hormone) that control insect growth and development. The characteristics of the mixed-function oxidases involved in the synthesis of insect hormones are described and the possibility that the enzymes might represent potential targets for insect control is discussed. Mixed-function oxidases constitute a group of evolutionarily ancient metalloproteins capable of catalyzing a wide variety of oxidative reactions in which one atom of molecular oxygen is inserted into an appropriate substrate and the other reduced to water (1). The Overall reaction typically involves the transfer of two electrons from a suitable reducing agent, often a reduced pyridine nucleotide (e.g., NADPH, NADH), and the formation of a highly reactive, electrophilic species of oxygen that is subsequently transferred to the substrate. Consequently, the main catalytic function of the enzymes is to activate molecular oxygen; the substrate to be oxidized plays a relatively passive role in the process (2). Mixed-function oxidases are ubiquitously distributed throughout the plant and animal kingdoms as well as in many aerobic procaryotes (3). They play a number of important biological roles and, indeed, are biochemically unique in their ability to catalyze the activation of non-activated carbon-hydrogen bonds. The following discussion will center on mixed-function oxidases involving the hemoprotein cytochrome P-450, the active center of which consists of protoporphyrin IX. Mixed-function oxidases based on cytochrome P-450 are perhaps best known for their role in the primary metabolism of lipophilic xenobiotics in mammals, birds, fish and many invertebrates including insects. While this function is often critical in determining the survival of an organism 0097-6156/85/0276-0161$06.00/0 © 1985 American Chemical Society

Hedin et al.; Bioregulators for Pest Control ACS Symposium Series; American Chemical Society: Washington, DC, 1985.

162

BIOREGULATORS FOR PEST CONTROL

following exposure to toxic chemicals and is frequently involved in insect resistance to insecticide chemicals (4), it will be discussed only briefly in this presentation. Most of the discussion will focus on the physiological role of cytochrome P-450-mediated mixed-function oxidases in the biosynthesis and regulation of the hormones controlling insect growth and development.


Xenobiotic Metabolism The oxidative enzymes involved in xenobiotic metabolism in insects are associated mainly with the microsomal fractions of the midgut and fat body, that are derived from the endoplasmic reticulum of the intact tissues (4-8). They catalyze the oxidative metabolism of a remarkable range of lipophilic compounds through reactions involving numerous functional groups; these reactions include aromatic, alicyclic and aliphatic hydroxylation reactions, dealkylation of ethers and substituted amines, epoxidation of double bonds and desulfuration of phosphorothionates. While the majority of these reactions constitute important detoxication pathways several can lead to enhanced biological activity through formation of reactive intermediates or products (9). All require NADPH and oxygen. The system depends on an electron transport pathway that transfers electrons from NADPH through a flavoprotein (NADPH cytochrome P-450 reductase) to cytochrome P-450 that is the terminal oxidase of the chain (10). The xenobiotic first forms a complex with the oxidized form of cytochrome P-450 which is reduced by an electron passing down the chain from NADPH. The reduced cytochrome P-450/substrate complex then reacts with and activates molecular oxygen to an electrophilic oxene species (an electron deficient species similar to singlet oxygen) that is transferred to the substrate with the concommitant formation of water. Cytochrome P-450 thus acts primarily as an oxene transferase {2). Substrate binding is a relatively nonspecific, passive process that serves to bring the xenobiotic into close association with the active center and provide the opportunity for the oxene transfer to occur. The unusual degree of nonspecificity of the xenobiotic-metabolizing cytochrome P-450 system results in part from the generally low level of specificity of the substrate binding sites at the active center of the cytochrome and in part from the existence of a number of isozymes of cytochrome P-450 each catalyzing a limited, perhaps overlapping spectrum of oxidative reactions with a variety of substrates (11). This has led to the development of the "cytochrome P-450 family" concept where the blend of isozymes may differ not only between different species but also between the different tissues of a single species (3,4). It is now generally believed that the cytochrome P-450 system that metabolizes xenobiotics has evolved specifically in response to selection pressure from the many naturally-occurring materials to which organisms are exposed in their diets or otherwise encounter in the environment (12). The ability of the enzymes to metabolize modern synthetic organic chemicals such as pesticides is simply a reflection of the evolutionary success that has been achieved in the development of a highly versatile system that is fully prepared for any eventuality (3,4,12).



10.

WILKINSON

Mixed-Function Oxidases

163

The mixed-function oxidases of mammals, insects and other organisms are remarkably well adapted for their role in biochemical defense. In addition to their metabolic versatility resulting from nonspecificity and the presence of numerous isozymes, the enzymes are located in those tissues that represent the major routes of entry of xenobiotics into the body. Furthermore, the ability of the enzymes to be induced enables organisms to make temporary qualitative and quantitative adjustments in the isozyme composition of their tissues to meet the ever changing challenges of their external chemical environment; this is clearly energetically advantageous since it precludes the necessity of maintaining high titers of enzyme protein at all times. It is particularly important to polyphytophagous insects since it allows them to adjust the composition of their protective enzymes depending on the host plant on which they are feeding (12). Role of Mixed-function Oxidases in Steroidogenic Reactions In addition to their obvious importance as a primary biochemical defense against a large variety of naturally occurring and synthetic lipophilic xenobiotics, mammalian mixed-function oxidases play a critical physiological role in the production and regulation of steroid hormones; it is becoming increasingly apparent that this is also true in insects. Since in comparative biochemistry, it is often the similarities rather than the differences that exist between organisms that are the most striking, a brief review of mammalian steroid hormone biosynthesis might be of both interest and relevance in interpreting the rather sparse information available with insects. The major sites of steroid hormone production in mammals are the adrenal cortex and the gonads, ( i . e . , the testis and the ovary). The major hormones synthesized and secreted by the adrenal cortex are the corticosteroids. These are of two types, the mineralocorticoids (e.g., aldosterone) that regulate fluid and ion balance, and the glucocorticoids (e.g, Cortisol) that control carbohydrate, fat and protein metabolism (Figure 1). The major hormones produced by the gonads are, of course, the sex hormones, androgens (primarily testosterone) in the male testis, and estrogens (e.g., estradiol) in the female ovary (Figure 1) (13). Since the major precursor of all of these hormones is cholesterol it becomes clear that, while the total biosynthetic routes are quite complex, they all involve a number of specific hydroxylation reactions involving both the steroid nucleus and the side chain at C-17. Most of these are catalyzed by mixed-function oxidases involving cytochrome P-450 (Figure 1) (13-15). The cytochome P-450 systems of the steroid producing tissues have many characteristics in common with those of the liver and other xenobiotic-metabolizing tissues. They require NADPH and molecular oxygen, and contain a flavoprotein, NADPH cytochrome P-450 reductase. Unlike the systems in the liver, however, the steroid hydroxylases are associated with both the endoplasmic reticulum and the mitochondria and are quite specific for the different reactions that they catalyze. Thus, adrenal microsomes




Figure 1. Cytochrome P-450-mediated hydroxylation reactions in biosynthesis of major mammalian steroid hormones. (MIT) = mitochondria; (ER) = endoplasmic reticulum.



10.

WILKINSON


165

contain 17a- and 21-hydroxylases while adrenal mitochondria cata lyze 11β- and 18-steroid hydroxylations as well as cholesterol side chain cleavage that is considered to be the primary rate-limiting step in mammalian steroidogenesis (14,16). The mitochondrial system differs markedly from that in adrenal microsomes in that the former contains an iron-sulfur protein (adrenodoxin) between the reductase and cytochrome P-450 and in that the adrenal flavoprotein is immunochemically distinct from that in the microsomal system; the latter appears identical with that in liver microsomes. In passing, it is interesting to note that the mitochondrial steroid hydroxylases of the mammalian endocrine system are remarkably similar to many of the procaryotic hydroxylases such as that in Pseudomonas putida that also contain iron-sulfur proteins (e.g., putidaredoxin) similar to adrenodoxin (13). As with the mixed-function oxidases involved in xenobiotic metabolism, the substrate specificity of the steroid hydroxylases is dictated, in part, by the existence of multiple forms of both microsomal and mitochondrial cytochrome P-450s and further oppor tunities for specificity are provided by the distinct localization of the various enzymes in either the mitochondria or the endoplas mic reticulum. While the hydroxylases of the adrenals and other steroid producing tissues show some (variable) catalytic activity towards xenobiotics (e.g., benzo[a]pyrene) (17) this is probably fortuitous in nature and it seems that, in general, the enzymes are quite specific for their respective steroid substrates. Furthermore, the steroid hydroxylases of the endocrine system are not susceptible to the inductive effects of xenobiotics as are the cytochrome P-450mediated oxidases of the liver and other tissues (17,18); indeed, this is not unexpected, since if they responded to the external environment in this way their critical homeostatic role would rapidly be compromized. In keeping with this role, the activity of the mixed-function oxidases in the mammalian producing steroid tissues is regulated primarily by a series of hormones that are released from the anterior pituitary in response to hormone releasing factors origi nating in the hypothalamus of the brain (Figure 2). The hormones controlling enzyme activities in the adrenal cortex, testis and ovary are the adrenal corticotropin hormone (ACTH), the f o l l i c l e stimulating hormone (FSH) and the luteinizing hormone (LH), respec tively. The arrival of these hormones at their appropriate endoc rine tissues serves to trigger the enzymes involved in steroid hydroxylation and in each case the metabolic process is initiated by the side chain cleavage of cholesterol that is stored in the tissues in the form of cholesterol esters (16). Steroidogenesis in Insects The steroids known to play major regulatory roles in insect develop ment and metamorphosis all fall into the class of polyhydroxylated ketosteroids called ecdysones (19-22). With the exception of Makisterone A (a C ecdysteroid identified from the milkweed bug Oncopeltus fasciatus) the known insect ecdysteroids constitute a group of eight or nine C steroids that differ from one another 2 g

? 7




CENTRAL

NERVOUS

SYSTEM

HYPOTHALAMUS

ANTERIOR

PITUITARY

/ Adrenal

corticotropin

(ACTH)

/ ADRENAL

ADRENAL

CORTEX

CORTICOIDS

Follicle

Luteinizing

stimulating

hormone (LH)

hormone ( F S H )

i TESTIS

ANDROGENS

\

OVARY

ESTROGENS

Figure 2. Hypothalamic-anterior pituitary regulation mammalian steroidogenesis (see text for explanation).


of


10.

167


WILKINSON

primarily in the number and position of the hydroxyl groups they contain; several others have been isolated but not yet fully identified. To date, interest in the ecdysteroids has focused primarily on their role in insect molting and metamorphosis and it is perhaps somewhat unfortunate that bioassays for ecdysteroid activity have been restricted almost exclusively to evaluating their effect on the molting process. It now appears probable that molting is just one of several important regulatory functions (e.g., embryogenesis, reproduction) performed by the ecdysteroids and that we are only just beginning to scratch the surface of an insect steroid system that is equally as complex as that in vertebrate species. The major ecdysteroids known to play a role in insect molting and/or metamorphosis are ecdysone, 20-hydroxyecdysone, and 20,26dihydroxyecdysone (Figure 3); 20-hydroxyecdysone (β-ecdysone) is the most active in terms of molting hormone activity. Ecdysones have been extracted in varying amounts from late larval and pupal stages of several lepidopteran species [e.g., Bombyx mori (23) and Manduca sexta (19-22)] as well as from the penultimate nymphal stages of several Fimimetabola such as Locusta migratoria (24), Schistocerca gregaria (25) and other species. 26-Hydroxyecdysone (Figure 3) has been identified as the major ecdysteroid (about 80% of total) present in embryonated eggs of Manduca, although it is devoid of molting hormone activity (20). This suggests that it might have an important embryogénie function or that it represents a metabolic degradation product of ecdysone. It is now well established that the predominant, perhaps only, source of ecdysone in larval insects is the prothoracic glands (19,20). Since, unlike mammals, insects are incapable of de novo synthesis of the steroid ring, the precursors of ecdysone must be one or more of several compounds, such as phytosteroids ingested in the diet (19-21). The precise pathway of ecdysone synthesis from precursors such as cholesterol remains unknown but clearly involves a number of steps including C desaturation (e.g., to dehydrocholesterol), C saturation, keto formation at C^, ci s fusion of the A/B rings, and a variety of hydroxylations at u , C,* C o and C p r . While dehydrocholesterol has not been detected in extracts from whole Manduca larvae, it has been extracted from the protharacic gland and may constitute 50% of the total steroids present in this organ (26). Although the exact sequence in which these ring hydroxylations take place is not clear and the enzymes responsible have not yet been characterized, it is generally thought that the last two reactions are at the 25- and 22- positions, respectively (Figure 4); another suggested pathway indicates the hydroxylation of 2-deoxyecdysone as the final step. The enzymes catalyzing these reactions have not yet been identified. It is probable, however, that they are cytochrome P-450 mediated and that they will be found to exhibit a good deal of regiospecificity with respect to the site of attack on the sterol molecule. One of these may be rate limiting as is the side-chain cleavage of cholesterol in mammalian steroidogenesis. The synthesis of ecdysone, the only ecdysteroid formed by the prothoracic glands, is under the control of the prothoracicotropic 7

&

2




Figure 4. Possible biosynthetic steroids to a-ecdysone.

pathway

from

dietary



10.

WILKINSON

169


hormone (PTTH) a peptide hormone that is produced by the neurosecretory cells of the brain and released by the corpora cardiaca (21). The fact that ecdysone synthesis can be initiated rapidly in response to PTTH suggests that the prothoracic gland may have the ability to sequester an appropriate ecdysone precursor (possibly 7-dehydrocholesterol or a conjugate) in a manner similar to the storage of cholesterol esters in the tissues of the mammalian endocrine system. It is not established whether ecdysone itself exerts any feedback control on the release of PTTH by the corpora cardiaca (21). While ecdysone, i t s e l f , may e l i c i t a general hormonal response affecting many tissues, i t is now well established that ecdysone is further metabolized to other, perhaps more active, ecdysteroids such as 20-hydroxyecdysone, 20,26-dihydroxyecdysone and 26-hydroxyecdysone in a number of specific tissues peripheral to the prothoracic gland. In this sense, ecdysone may be serving as a prohormone that can be metabolically activated to a variety of derivatives each regulating the specific endocrine functions of one or more target organs. Indeed, ecdysone may serve primarily as a general precursor for the synthesis of other ecdysteroids and may be sequestered in specific target tissues in inactive form until required. Balance between the active and inactive forms of ecdysone and/or other ecdysteroids may be accomplished by the formation of conjugates such as sulfate esters or glucosides (20,27). The sulfation of phenols and a variety of sterols has beenTemonstrated in insect tissues and this, in close association with an appropriate sulfatase, would constitute a readily reversible mechanism whereby the required balance between active and inactive forms of ecdysteroids could be regulated (27). The further metabolism of ecdysone to other more active or less active ecdysteroids constitutes another potential mechanism for hormone regulation and it is likely that many of the hydroxylation reactions involved are catalyzed by cytochrome P-450-mediated mixed function oxidases (Figure 5). Since the enzyme ecdysone 20-hydroxylase catalyzes the conversion of ecdysone to the more potent molting hormone 20-hydroxyecdysone (Figure 5), it has received considerable attention in recent years. Ecdysone 20-hydroxylase activity has been measured in the tissues of a number of insect species; these include the fat body and several other tissues of lepidopterous larvae such as Manduca sexta (19,20,28,29) and the midgut, fat body and Malpighian tubules of penultimate nymphal instars of Locusta migratoria (24,30) and Schistocerca gregaria (25). Most of these studies have established that the enzyme is located in the mitochondrial fraction of tissue homogenates, although the enzyme in the fat body and Malpighian tubules of Locusta is reportedly associated with the microsomal fraction (30). All studies concur that the enzyme is a cytochrome P-450-mediated mixed-function oxidase and its requirements for NADPH and 0 and sensitivity to inhibitors such as carbon monoxide, metyrapone, e t c . , support this conclusion. As yet, there are no reports as to whether the enzyme is associated with an iron sulfur protein similar to the adrenodoxin of the mammalian mitochondrial steroid 2



170


synthesis system although it is entirely probable that such a component will eventually be identified. It is generally assumed that the cytochrome P-450s involved in steroidogenesis exhibit a considerably greater degree of substrate specificity than their counterparts involved in xenobiotic metabolism and certainly this is true for the mammalian enzymes. From the results of limited studies based on the ability of various ecdysteroids to competitively inhibit the conversion of ecdysone to 20-hydroxyecdysone in vitro by the Manduca fat body mitochondrial enzyme, it has been concluded that the enzyme is not highly specific for ecdysone {19). However, this is not a conclusive test for substrate specificity and may have l i t t l e or no relevance to the situation occurring under physiological conditions in the intact cell. At the present time, ecydsone 20-hydroxylase is the only major ecdysteroid synthesizing enzyme that has been isolated and characterized to any extent from insect tissues and its regulatory role, i f any, has not been established. While the prothoracic gland appears to be the only tissue capable of synthesizing ecdysone in immature insects, ecdysone and several other ecdysteroids are also produced by the ovary in adult female insects (31). In most species this occurs at the end of oocyte maturation and seems to be controlled by a foiliculotropic factor released by the corpara cardiaca. Ecdysone synthesis appears to occur de novo from cholesterol and ecdysone and possibly other ecdysteroids are stored in the oocyte tissue as polar conjugates rather than being released into the blood {31). It seems probable that ovarian synthesis of ecdysone is the major source of the various ecdysteroids (20-hydroxyecdysone, 26-hydroxyecdysone, 20,26-di hydroxyecdysone, 2-deoxyecdysone and 3-dehydroecdysone) that have been identified in insect eggs and developing embryos. These hormones derived from the adult female may well control critical events in the early stages of embryonic development prior to the development of the embryonic prothoracic gland. At least, one of the functions of embryonic ecdysteroids may be the control of cuticulogenesis (31). Insect ecdysteroids may also play an important role in the hormonal control of reproduction (31,34). Thus, in the case of the mosquito, Aedes aegypti, ecdysone appears to be responsible for stimulating the synthesis of vitellogenin (egg protein) by the fat body (32,33). The source of the ecdysone in this case is again the ovary and ecdysone biosynthesis is initiated in response to a neurosecretory hormone (EDNH, egg development neurosecretory hormone) released following ingestion of the blood meal (34). As in the case of the ecdysone sequestered in the eggs, the mosquito ovary appears to synthesize ecdysone de novo from cholesterol. In the latter case, however, the ecdysone is released into the blood, and passed to the fat body where it is converted into 20-hydroxyecdysone and possibly other ecdysteroids before stimulating v i t e l logenin synthesis. While not yet studied at the enzymatic level, i t is almost certain that one or more cytochrome P-450-mediated monooxygenases are involved in the ovarian synthesis of ecdysone and may thus play an important regulatory role in reproductive maturation in adult female insects. It is possible that ecdysone


10.

WILKINSON


171


also plays a role in the reproductive maturation in male insects since the testes of last-instar larvae of the tobacco budworm effect the synthesis and release of several ecdysteroids (35). The similarities between ecdysone synthesis in the insect prothoracic gland and the ovary are obvious and in each case synthesis is initiated in response to a hormone originating in the brain* Both bear a striking resemblance to the mammalian system where steroid hormone synthesis in the various endocrine tissues is initiated in response to the release of appropriate hormones from the anterior pituitary. Juvenile Hormone The molting and other hormonal activities of the ecdysteroids are, of course, modulated by the titer of the insect juvenile hormone and the two materials typically function in close concert with one another in dictating insect molting and metamorphosis as well as in reproductive maturation (21). The three major, known insect juvenile hormones (JH I, JH II and JH III) (Figure 6) are all methyl esters of terminally epoxidized homologs of farnesoic acid. They are present in varying amounts in different insects at different stages of development and i t has been suggested, though not determined, that they may play different hormonal roles. The juvenile hormones are synthesized and rapidly released into the hemolymph from the neuroendocrine glands known as the corpora allata; synthesis appears to be under control of a hormone originating in the brain. The farnesoic acid precursors of the juvenile hormones are synthesized by appropriate isoprenoid routes from acetyl CoA and/or propionyl CoA and subsequently undergo 10,11-epoxidation and methylation of the carboxylic acid group by ^-methyl transferase (36) (Figure 7). It is not yet fully ascertained whether in vivo farnesoic acid is epoxidized prior to methylation or whetfïër the order of these two terminal reactions is reversed. The epoxidase catalyzing the 10,11-epoxidation of methyl farnesoate in homogenates of corpora allata from Locusta migratoria has been studied in detail and has been shown to be a cytochrome P-450-mediated monooxygenase associated with the microsomal fraction. The enzyme is strictly dependent on NADPH and requires oxygen (36). It is sensitive to inhibition by carbon monoxide (36) and to other compounds such as methylenedioxyphenyl compounds and imidazoles that are well established inhibitors of the cytochrome P-450-mediated monooxygenases involved in xenobiotic metabolism (37-39). In recent years, considerable attention has been given to the possibility of developing synthetic inhibitors of juvenile hormone synthesis (anti-juvenile hormones) that would result in a lethal block of JH synthesis. Although a large number of compounds have been screened as potential anti-juvenile hormone agents and several have been found to be effective inhibitors j m vitro, few have exhibited significant jn. vivo morphogenetic activity. The possibility of causing premature metamorphosis and lethality through chemical allatectomy has been given further impetus, however, by



B I O R E G U L A T O R S F O R PEST C O N T R O L

20-HYDROXYECDYSONE

Figure 5.

20.26-DIHYDROX YECD YSONE

Further hydroxylative metabolism of ecdysone.

JH-III Figure 6.

Insect juvenile hormones.



10.

WILKINSON


173

the finding that, in sensitive species, the anti-allatal precocenes (40) are bioactivated by the cytochrome P-450 system of the corpora allata to potent cytotoxins that result in irreversible necrosis of the corpora allata. The mechanism of bioactivation appears to be the formation of a highly reactive electrophilic 3,4-epoxide that immediately alkylates critical macromolecular site(s) in the corpora allata (42) (Figure 8). The suicidal bioactivation of the precocenes clearly suggests the possibility that, while the cytochrome P-450 system involved in JH synthesis may be quite specific with respect to the substrates it will accept, it represents a potentially important and viable target for future pest control agents.

Summary In conclusion, mixed-function oxidases based on cytochrome P-450 are extremely important to insects, not only in providing a measure of protection against a wide variety of naturally occurring and synthetic xenobiotics, but also in the biosynthesis of the hormones that determine the complex patterns of insect growth, development and sexual maturation. While the mixed-function oxidases involved in hormone biosynthesis have not yet been characterized in any detail, it is probable that like the enzymes involved in mammalian steroidogenesis, they will be found to differ from those involved in xenobiotic metabolism in both substrate specificity and in the regulatory mechanisms through which they are controlled. It seems inconceivable, for example, that the enzymes involved in hormone synthesis are inducible by xenobiotics since this would destroy homeostatic control and in effect would open up critical physiological development to the whims of the external environment; clearly, this does not occur. Instead, the enzymes are undoubtedly regulated by a variety of endogenous factors (hormones) released from the central neuroendocrine system in response to a variety of endogenous and exogenous stimuli. In view of their critical importance in regulating the growth and development of insects, the enzymes should continue to be viewed as potentially valuable targets around which to develop new pest control agents. This possibility is likely to become more realistic as the enzymes are further characterized and the full extent of their many roles in insect development are more fully understood.



Isopentenyl pyrophosphate

COPOP

Farnesoic acid pyrophosphate Downloaded by UNIV OF MASSACHUSETTS AMHERST on October 24, 2017 | http://pubs.acs.org Publication Date: April 26, 1985 | doi: 10.1021/bk-1985-0276.ch010

O-METHYL TRANSFERASE (S-adenosylmethionine)

^^COoCHo

Methyl farnesoate CYTOCHROME P-450 (NADPH, oxygen) C0 CH 2

JH-III Figure 7. Biosynthesis of insect juvenile hormone

III.

CH '

if

>-CH

3

farnesoate epoxidase

PRECOSENE 1

3,4-DIHYDROPRECOSENE 1 '3,4-EPOXIDE

A L K Y L A T I O N O F CRITICAL MACROMOLECULAR

SITES

chemical allatectomy

Figure 8. Bioactivation of precocene I.


3

10. WILKINSON


175

Literature Cited


1.

Mason, H. S. In "Homologous Enzymes and Biochemical Evolu tion"; Thoai, N.V. and Roche, J . , Eds.; Gordon and Breach: New York, 1968; pp. 69-91. 2. Trager, W. F. In "Concepts in Drug Metabolsim"; Jenner, P. and Testa, B . , Eds.; Marcell Dekker: New York, 1981; Part A, Chap. 3. 3. Wilkinson, C. F . , In "The Scientific Basis of Selective Toxicity"; Witschi, H. R., Ed.; Elsevier/North Holland: Amsterdam, 1980; pp. 251-268. 4. Wilkinson, D. F . , In "Pest Resistance to Pesticides"; Georghiou, G. P. and Saito, T . , Eds; Plenum: New York, 1983; pp. 175-205. 5. Agosin, M. and Perry, A. S. In "The Physiology of Insecta"; Rockstein, M., Ed.; Academic: New York, 1974; Vol. V . , pp. 537-596. 6. Hodgson, E. and Plapp, F. W. J . Agr. Food Chem. 1970, 1048-1052. 7. Wilkinson, C. F. and Brattsten, L. B. Drug Metab. Revs. 1972, 1, 153-228. 8. Wilkinson, C. F. In "Xenobiotic Metabolism: In Vitro Methods"; Paulson, G. D., Frear, D. S. and Marks, E. P., Eds.; ACS SYMPOSIUM SERIES No. 97, American Chemical Society: Washington, D.C. 1979; pp. 249-284. 9. Cummings, S. W. and Prough, R. A. In "Biological Basis of Detoxication"; Caldwell, J . and Jakoby, W. B . , Eds.; Academic: London, 1983; Chap. 1. 10. Estabrook, R. W., Werringloer, J . and Peterson, J . A. In "Xenobiotic Metabolism: In Vitro Methods"; Paulson, G. D., Frear, D. S. and Marks, E. P., Eds.; ACS SYMPOSIUM SERIES No. 97, American Chemical Society: Washington, D. C. 1979; pp. 149-179. 11. Lu, A.Y.U. and West, S. B. Pharmacol. Revs. 1980, 31, 277-295. 12. Brattsten, L. B. In "Herbivores: Their Interaction with Secondary Plant Metabolites"; Rosenthal, G. A. and Janzen, D. H . , Eds.; Academic: New York; 1979; pp. 199-270. 13. Armstrong, F. B. "Biochemistry"; Oxford University Press: Oxford, 1979; p. 386. 14. Gunsalus, I. C . , Pederson, T. C. and Sligar, S. G. Ann, Rev. Biochem. 1975, 44, 377-407. 15. Dempsey, M. E. Ann. Rev. Biochem. 1974, 43, 967-990. 16. Boyd, G. S. and Trzeciak, W. H. In "Multienzyme Systems in Endocrinology: Progress in Purification and Methods of Inves tigation"; Cooper, D. Y. and Salhanick, Η. Α . , Eds.; Annals N.Y. Academy Sciences: New York, 1973; Vol. 212, pp. 361-377. 17. Guenther, T. M. and Nebert, D. W. Mol. Pharmacol. 1979, 15, 719-728. 18. Feuer, G . , Sosa-Lucero, J . C . , Lumb, G. and Moddel, G. Toxicol. Appl. Pharmacol. 1971, 19, 579-585. 19. Smith, S. L . , Bollenbacher, W. E. and Gilbert, L. K. In "Progress in Ecdysone Research"; Hoffmann, J . Α . , Ed.; E l sevier/North Holland: Amsterdam, 1980; pp. 139-162.



176

20.

21.


22.

23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42.

Kaplanis, J. N., Weirich, G. F., Svoboda, J. Α., Thompson, M. J. and Robbins, W. E. In "Progress in Ecdysone Research"; Hoffmann, J. Α., Ed.; Elsevier/North Holland: Amsterdam, 1980; 163-186. Riddiford, L. M. and Truman, J. W. In "Biochemistry of Insects"; Rockstein, M., Ed.; Academic: New York; 1978, Chap. 7. Thompson, M. J., Kaplanis, J. N., Weirich, G. f., Svoboda, J. A. and Robbins, W. E. Proc. International Conference on Regulation of Insect Development and Behavior; Wroclaw Tech nical Univ.: Poland, 1981; Conf. No. 7, pp. 107-124. Chino, H., Sakurai, S., Ohtaki, T., Ikekawa, N., Miyazaki, H., Ishibashi, M. and Abuki, H. Science 1974, 183, 529-530. Feyereisen, R. and Durst, F. Mol. Cell. Endocrinol. 1980, 20, 157-169. Johnson, P. and Rees, H. H. Biochem. J. 1977, 168, 513-520. Thompson, M. J., Kaplanis, J. N., Robbins, W. E. and Svoboda, J. A. Adv. Lipid Res. 1973, 11, 219-265. Yang, R.S.H. and Wilkinson, C. F. Biochem. J. 1972, 130, 487-493. Mayer, R. T., Svoboda, J. A. and Weirich, G. F. Hoppe-Seyler's Z. Physiol. Chem. 1978, 359, 1247-1257. Bollenbacher, W. E., Smith, S. L., Wielgus, J. J. and Gilbert, L. I. Science 1977, 268, 660-663. Feyereisen, R. and Durst, F. Eur. J. Biochem. 1978, 88, 37-47. Hoffmann, J. Α., Lageux, M., Hetru, C., Charlet, M. and Goltzene, F. In "Progress in Ecdysone Research"; Hoffman, J. Α., Ed.; Elsevier/North Holland: Amsterdam, 1980; pp. 431-465. Hagedorn, H. H. and Fallon, A. M. Nature 1973, 244, 103-105. Hagedorn, H. H., O'connor, J. D., Fuchs, M. S., Sage, B., Schlaeger, D. A. and Bohm, M. K. Proc. Nat. Acad. Sci. U.S.A. 1975, 72, 3255-3259. Hanaoka, K. and Hagedorn, H. H. In "Progress in Ecdysone Research"; Hoffmann, J. Α., Ed.; Elsevier/North Holland: Amsterdam, 1980; pp. 467-480. Loeb, M. J., Woods, C. W., Brandt, E. P. and Borkovec, A. B. Science 1982, 281, 896-898. Feyereisen, R., Pratt, G. E. and Hamnett, A. F. Eur. J. Biochem. 1981, 118, 231-238. Hammock, B. D. and Mumby, S. M. Pestic. Biochem. Physiol. 1978, 9, 39-47. Brooks, G. T., Pratt, G. E. Ottridge, A. P. and Mace, D. W. Proc. Brit. Crop Protection Conf. 1984, in press. Feyereisen, R., Langry, K. C. and Ortiz de Montellano, P. R. Insect Biochem. 1984, 14, 19-26. Bowers, W. S., Ohta, T., Cleere, J. S. and Marsella, P. A. Science 1976, 193, 542-547. Masner, P., Bowers, W. S., Kalin, M. and Muhle, T. Gen Comp Endocrinol. 1979, 37, 156-166. Hamnett, A. F., Ottridge, A. P. Pratt, G. E., Jennings, R. C. and Stott, Κ. M. Pestic. Sci. 1981, 12, 245-254.

RECEIVED November 15, 1984


Role of Mixed-Function Oxidases in Insect Growth and Development

Recommend Documents