Cytochrome P450: A Target for Drug Development for Skin Diseases
2004; Elsevier BV; Volume: 123; Issue: 3 Linguagem: Inglês
10.1111/j.0022-202x.2004.23307.x
ISSN1523-1747
Autores Tópico(s)Cancer Treatment and Pharmacology
ResumoEnzymes of the cytochrome P450 (P450 or CYP) super family are the most versatile and important class of drug-metabolizing enzymes that are induced in mammalian skin in response to xenobiotic exposure. At the same time, CYP have numerous important roles in endogenous and exogenous substrate metabolism in the skin. For example, they participate in the metabolism of therapeutic drugs, fatty acids, eicosonoids, sterols, steroids, vitamin A, and vitamin D, to name a few. In addition, in some skin diseases, for example in psoriasis, many CYP are elevated. CYP are the target of special interest in the development of drugs for skin diseases because most, if not all, drugs available in the armamentarium of the dermatologists are either substrate, inducer, or inhibitor of this enzyme family. The functional significance of drug metabolism in skin and the implication of CYP in skin pathology and therapy is an area for future investigation. A detailed insight into the mechanism of action of various cutaneous CYP, being capable of modulating the drug bioavailability, will be helpful in the development of better strategies for novel therapy against constantly increasing skin disorders. This brief review discusses some of these perspectives and suggests additional work in this research area with regard to the expression and modulation of CYP in mammalian skin as well as their implication in dermatological disorders and the therapy of skin diseases. Enzymes of the cytochrome P450 (P450 or CYP) super family are the most versatile and important class of drug-metabolizing enzymes that are induced in mammalian skin in response to xenobiotic exposure. At the same time, CYP have numerous important roles in endogenous and exogenous substrate metabolism in the skin. For example, they participate in the metabolism of therapeutic drugs, fatty acids, eicosonoids, sterols, steroids, vitamin A, and vitamin D, to name a few. In addition, in some skin diseases, for example in psoriasis, many CYP are elevated. CYP are the target of special interest in the development of drugs for skin diseases because most, if not all, drugs available in the armamentarium of the dermatologists are either substrate, inducer, or inhibitor of this enzyme family. The functional significance of drug metabolism in skin and the implication of CYP in skin pathology and therapy is an area for future investigation. A detailed insight into the mechanism of action of various cutaneous CYP, being capable of modulating the drug bioavailability, will be helpful in the development of better strategies for novel therapy against constantly increasing skin disorders. This brief review discusses some of these perspectives and suggests additional work in this research area with regard to the expression and modulation of CYP in mammalian skin as well as their implication in dermatological disorders and the therapy of skin diseases. arachidonic acid aryl hydrocarbon hydroxylase benzo(a)pyrene cytochrome P450 CYP side chain cleavage 1,25-dihydroxyvitamin D(3) 7-ethoxycoumarin deethylase 7-ethoxyresorufin deethylase leukotrienes β-naphthoflavone polycyclic aromatic hydrocarbons retinoic acid ultraviolet Skin is the largest organ of the body that is exposed, both acutely and chronically, to a variety of chemicals either intentionally through drugs and cosmetics, or unintentionally as a result of exposure to environmental pollutants such as industrial chemicals and pesticides. This culminates into a variety of skin-related occupational health problems. For this reason, the National Institute of Occupational Safety and Health has categorized the skin diseases as one of the most pervasive occupational health problems in the USA (Rice and Cohen, 1996Rice R.H. Cohen D.E. Toxic response of skin.in: Klassen C.D. Toxicology: The Basic Science of Poison. McGraw-Hill, New York1996: 529-546Google Scholar). In response to this issue, one major focus of health-care professionals and researchers is to design mechanism-based approaches aimed at the prevention and cure for this chronic problem. For this reason, a proper understanding of the mechanisms involved in the biotransformation of xenobiotics by the skin is of utmost importance. The xenobiotics that come in contact with the skin are biotransformed into harmless or less harmful agents by enzymatic reactions catalyzed by a variety of metabolizing enzymes present in the skin. Cytochrome P450 (P450 or CYP), the key metabolic enzyme family, is the terminal oxidase of the mixed function oxygenase system capable of metabolizing drugs and chemicals in hepatic and extrahepatic tissues including skin (Gonzales, 1989Gonzales F.J. The molecular biology of cytochrome P-450s.Pharmacol Rev. 1989; 40: 243-288Google Scholar). Humans have 57 functional CYP genes and 46 pseudogenes (http://www.drnelson.utmem.edu/human.genecount.html). Ironically, certain xenobiotics which themselves are not carcinogenic are biotransformed by cutaneous CYP into proximate or ultimate carcinogens (Mukhtar et al., 1991Mukhtar H. Agarwal R. Bickers D.R. Cutaneous metabolism, of xenobiotics and steroid hormones.in: Mukhtar H. Pharmacology of the Skin. CRC Press, Boca Raton, FL1991: 89-109Google Scholar and references therein). The special interest for CYP enzymes in skin is evident by the fact that most, if not all, drugs used by the practicing dermatologist are either substrate or inducer, or inhibitor of this enzyme family (Table I). It is important to mention here that CYP enzymes act on many endogenous substrates including vitamin D and vitamin A, which are widely used in clinical practice for treating a variety of dermatological disorders. Also, many ingredients in cosmetics, toiletries, and health-care products, as well as a number of allergens, toxicants, and carcinogens to which the skin is exposed, serve as substrates for CYP. In this review, we present a brief account of the research of cutaneous CYP with emphasis on its role in drug development for skin diseases.Table ISubstrates, inhibitors, and inducers of cytochrome P450 used for skin diseasesaThis list, by no means, is complete.SubstratesInhibitorsInducersAntihistaminesClotrimazoleCyclosporinChloroquineGriseofulvinDexamethasoneCrude coal tarItraconazoleCrude coal tarCyclosporinKetoconazolePsoralensDapsoneLiarazoleretinoid acidGlucocorticoidsMiconazoleRifampicinGriseofulvinPsoralensUltraviolet lightHydroxychloroquineRetinoic acidImidazolesVoriconazolePsoralensRetinoic acidSteroidsVitamin Da This list, by no means, is complete. Open table in a new tab The first known prokaryotes were autotrophic and anaerobic in nature, and it is believed that the photosynthetic bacteria existed about 3500 million years ago. The photosystem-I, used by the anaerobic photosynthetic bacteria, was not capable of producing oxygen (O2) and therefore they depended on hydrogen sulfide (H2S), hydrogen (H2), and/or organic molecules for electron donation. On the other hand, the photosystem-II, which existed in Archean cyanobacteria, used water as electron donor and is believed to be the source of today's oxygen. About 3000 million years ago, our planet got rusted because of the oxidation of sulfides, iron, and organics. At this time, the prokaryotes were successfully adapting for aerobic life. A massive increase in the atmospheric oxygen occurred about 2200 million years ago that resulted in the evolution of symbiotic eucaryotes as well as the enzyme CYP, capable of detoxifying the atmospheric oxygen. Finally, as a result of limited mutations, the modern CYP evolved in the living system (Nebert and Feyereisen, 1994Nebert D.W. Feyereisen R. Evolutionary argument for a connection between drug metabolism and signal transduction.in: Lechner M.C. Biophysics and Molecular Biology, Proceedings of the 8th International Conference, Cytochrome P450, Biochemistry Eurotex, Paris1994: 3-13Google Scholar). The first experimental evidence of the discovery of CYP dates back to the year 1955, when an enzyme system capable of oxidizing xenobiotic compounds was identified in the endoplasmic reticulum of the liver (Axelrod, 1955Axelrod J. The enzymatic demethylation of ephidrine.J Pharmacol. 1955; 114: 430-438Google Scholar;Brodie et al., 1955Brodie B. Axelrod J. Cooper J.R. et al.Detoxication of drugs and other foreign compounds by liver microsomes.Science. 1955; 121: 603-604Crossref PubMed Scopus (85) Google Scholar). In the year 1958, two independent studies (Garfinkel, 1958Garfinkel D. Studies on pig liver microsomes. I. Enzymic and pigment composition of different microsomal fractions.Arch Biochem Biophys. 1958; 77: 493-509Crossref PubMed Scopus (274) Google Scholar;Klingenberg, 1958Klingenberg M. Pigments of rat liver microsomes.Arch Biochem Biophys. 1958; 75: 376-386Crossref PubMed Scopus (441) Google Scholar) detected a carbon monoxide (CO)-binding pigment in liver microsomes, which had an absorption maximum at 450 nm. This was demonstrated to be a hemoprotein of the b-type class in 1964 (Omura and Sato, 1964aOmura T. Sato R. The carbon monoxide-binding pigment of liver microsomes. I. Evidence for its hemoprotein nature.J Biol Chem. 1964; 239: 2370-2378Abstract Full Text PDF PubMed Google Scholar, Omura and Sato, 1964bOmura T. Sato R. The carbon monoxide-binding pigment of liver microsomes. II. solubilization, purification and properties.J Biol Chem. 1964; 239: 2378-2385Google Scholar), which was given its classical name after the strong feature in its absorption spectrum. CYP are categorized based upon their amino acid sequence similarities and are grouped in families, which are made up of subfamilies. The cytochromes, P450, are named with the root CYP followed by a number designating the family, a capital letter that belongs to the subfamily and a number for the individual form. Thus, CYP1A1 denotes family “1”, subfamily “A” and “1”. The genes are also designated in a similar fashion, but in italics: CYP1A1. “CYP” describes the members of an enzyme superfamily that catalyzes the oxidative biotransformation of more harmful lipophilic substrates to less harmful or harmless hydrophilic metabolites for their ultimate removal from the living system. CYP are mostly located in the endoplasmic reticulum, and to some extent in mitochondrial fractions of hepatic and extra-hepatic tissues, including skin. Structurally, CYP are heme-containing proteins consisting of iron in its +3 oxidation state. The Fe3+, on reduction, is converted to Fe2+ that facilitates the binding of CYP with ligands such as O2 and CO. The complex between Fe2+ (of P450) and CO absorbs at 450 nm and this is the reason for the classical name, “CYP”. The first experimental evidence for the existence of CYP proteins was obtained in 1958 when this pigment was characterized in pig and rat liver microsomes (Mukhtar et al., 1991Mukhtar H. Agarwal R. Bickers D.R. Cutaneous metabolism, of xenobiotics and steroid hormones.in: Mukhtar H. Pharmacology of the Skin. CRC Press, Boca Raton, FL1991: 89-109Google Scholar and references therein). Since then, a considerable amount of work has been done in defining the role of these enzymes and their functions and at present the human genome is known to encode 57 CYP proteins. The majority of CYP are involved in the metabolism of steroids, bile acids, fatty acids, eicosanoids, and fat soluble vitamins. About 15 P450 are known to be involved in the metabolism of drugs and other xenobiotic chemicals and have received attention for drug development. It is clear now that no enzyme of this family possesses a unique substrate specificity and may perform more than one catalytic function on more than one substrates. Similarly, multiple CYP may act on one chemical or substrate. The classical reaction catalyzed by CYP is “monooxygenation”, where one atom of oxygen (of O2) is incorporated into a substrate whereas the other oxygen atom is reduced to water using an electron from NADPH as follows:R+O2+NASPH+H+→RO+H2O+NADP+(where R is the substrate and RO the product) The metabolism of drug, in general, consists of two phases defined as phase-I and phase-II. Phase-I includes the reactions resulting in the incorporation of a polar reactive group into the inert molecule which, in turn, becomes the substrate for phase-II enzymes. In general, CYP-dependent reactions result in detoxification of a pharmacologically active drug into its inactive forms, but a number of examples also exist where the inert carcinogenic agents, generally referred to as “precarcinogens”, are metabolized into proximate or ultimate carcinogens by the CYP system. Benzo(a)pyrene (BaP), present in crude coal tar widely used in dermatology and also generated by the incomplete combustion of fossil fuel, a ubiquitous pollutant, is an excellent example of this type of reaction (Conney, 1982Conney A.H. Induction of microsomal enzymes by foreign chemicals and carcinogenesis by polycyclic aromatic hydrocarbons: GHA Clowes Memorial Lecture.Cancer Res. 1982; 42: 4875-4917PubMed Google Scholar). The metabolic products formed in phase-I undergo conjugation reactions with glucuronide, sulfate, glutathione, etc. in phase-II metabolism. The product of this reaction is generally hydrophilic and is readily excreted out from the body. The CYP, in addition to the hydroxylation reactions, also oxidize the heteroatoms including nitrogen and sulfur. The CYP-mediated oxidation of aliphatic double bonds or aromatic hydrocarbons leads to the formation of epoxides, which may either be labile intermediates or stable products. These epoxides can then be converted into dihydroxy metabolites known as “diols”, by the hydrolysis reactions either non-enzymatically using water or by an enzymatic reaction catalyzed by epoxide hydrolase (Conney, 1982Conney A.H. Induction of microsomal enzymes by foreign chemicals and carcinogenesis by polycyclic aromatic hydrocarbons: GHA Clowes Memorial Lecture.Cancer Res. 1982; 42: 4875-4917PubMed Google Scholar). The barrier function of the skin is evident from its ability to metabolize the agents, which diffuse through it, leading to their altered biological activities. The xenobiotics, to which the skin is exposed, and the topically applied drugs may undergo a degradation or activation process, which may result in skin sensitization or even carcinogenesis. The CYP are the most important among the drug-metabolizing enzymes in the skin, by virtue of their crucial role in controlling the steady-state concentrations of a variety of bioactive substances including fatty acids, steroids, prostaglandins, glucocorticoids, retinoids, and leucotrienes (LT) (Mukhtar and Khan, 1989Mukhtar H. Khan W.A. Cutaneous cytochrome P450.Drug Metab Rev. 1989; 20: 657-673Crossref PubMed Scopus (44) Google Scholar; and references therein). Being capable of modulating the drug bioavailability in the skin, the CYP are important targets for the development of better strategies for the therapy of skin disorders. Skin is a heterogenous tissue consisting of several structural proteins and therefore resistant to the conventional preparative processes, and the enzyme activities are also much lower in skin than in most other tissues. In 1953, Norden showed that following cutaneous application of benzopyrene to guinea-pigs, a metabolic fluorescence appeared in the epidermis, hair follicles, and sebaceous glands of the skin, suggesting the occurrence of metabolism in the skin (Mukhtar et al., 1991Mukhtar H. Agarwal R. Bickers D.R. Cutaneous metabolism, of xenobiotics and steroid hormones.in: Mukhtar H. Pharmacology of the Skin. CRC Press, Boca Raton, FL1991: 89-109Google Scholar; and references therein). Since then, a considerable body of work, from many laboratories including ours, has been done in the area of CYP and drug metabolism in the skin (Mukhtar et al., 1991Mukhtar H. Agarwal R. Bickers D.R. Cutaneous metabolism, of xenobiotics and steroid hormones.in: Mukhtar H. Pharmacology of the Skin. CRC Press, Boca Raton, FL1991: 89-109Google Scholar; and references therein). RT-PCR, immunoblot, immunohistochemistry, and catalytic assays revealed that proliferating normal human skin keratinocytes show the expression of various CYP enzymes, especially CYP1A1, CYP1B1, CYP2B6, CYP2E1, and CYP3A. In comparison with other cells present in human skin, e.g., monocytes (Baron et al., 2001Baron J.M. Holler D. Schiffer R. et al.Expression of multiple cytochrome p450 enzymes and multidrug resistance-associated transport proteins in human skin keratinocytes.J Invest Dermatol. 2001; 116: 541-548Crossref PubMed Scopus (209) Google Scholar and references therein), lymphocytes (Baron et al., 2001Baron J.M. Holler D. Schiffer R. et al.Expression of multiple cytochrome p450 enzymes and multidrug resistance-associated transport proteins in human skin keratinocytes.J Invest Dermatol. 2001; 116: 541-548Crossref PubMed Scopus (209) Google Scholar and references therein), and fibroblasts (not published), considerably higher amounts of these enzymes were found to be present in keratinocytes. By immunofluorescent techniques, CYP1A1, CYP2B6, CYP2E1, and CYP3A were found to be expressed dominantly in keratinocytes compared with fibroblasts (Baron et al., 2001Baron J.M. Holler D. Schiffer R. et al.Expression of multiple cytochrome p450 enzymes and multidrug resistance-associated transport proteins in human skin keratinocytes.J Invest Dermatol. 2001; 116: 541-548Crossref PubMed Scopus (209) Google Scholar and references therein). Among various CYP, CYP1A1 is the best conserved of all the xenobiotic metabolizing enzymes and is one of the few CYP that are known to be expressed in skin. The constitutive levels of CYP1A1 in skin are too low to be measured without an exposure to some exogenous inducer. CYP1A1, despite of being well conserved throughout the animal kingdom, is not known to possess any unique endogenous substrate. The various polycyclic aromatic hydrocarbons (PAH), such as BaP, 3-methylcholanthrene, or 7,12-dimethylbenz(a)anthracene, are excellent substrates for CYP1A1. The CYP1A1-mediated reactions result in mutagenic and carcinogenic metabolites of the parent compounds. Several studies have demonstrated the inductibility of CYP1A1 and the related monooxygenase activities, in human and rodent skin as well as human hair follicles, following the exposure to PAH, β-naphthoflavone (β-NF), and glucocorticoid (Mukhtar and Bickers, 1983Mukhtar H. Bickers D.R. Age related changes in benzo(a)pyrene metabolism and epoxide metabolizing enzyme activities in rat skin.Drug Metab Dispos. 1983; 11: 562-567PubMed Google Scholar;Finnen et al., 1984Finnen M.J. Herdman M.L. Shuster S. Induction of drug metabolizing enzymes in the skin by topical steroids.J Steroid Biochem. 1984; 20: 1169-1173Crossref PubMed Scopus (14) Google Scholar;Merk et al., 1987Merk H.F. Mukhtar H. Kaufman I. et al.Human hair follicle benzo(a)pyrene and benzo(a)pyrene 7,8-diol metabolism: Effect of exposure to a coal tar containing shampoo.J Invest Dermatol. 1987; 88: 71-76Abstract Full Text PDF PubMed Google Scholar;Whitlock, 1987Whitlock J.P. The regulation of cytochrome P450 gene expression.Annu Rev Pharmacol Toxicol. 1987; 26: 333-369Crossref Google Scholar). Further, the induction of CYP1A1 mRNA, in rat epidermis, and cultured human epidermal keratinocytes by benz(a)anthracene, and β-NF has been shown using a RT-linked PCR (Khan et al., 1992Khan I.U. Bickers D.R. Haqqi T.M. et al.Induction of CYPIAl mRNA in rat epidermis and cultured human epidermal keratinocytes by benz(a)anthracene and β-naphthoflavone.Drug Metab Dispos. 1992; 22: 620-624Google Scholar). The treatment, with these inducers, was found to result in several-fold enhancement in aryl hydrocarbon hydroxylase (AHH) activity in rat epidermis as well as in human keratinocytes. The exposure to β-NF and BaP also resulted in a significant enhancement of AHH activity in rat epidermis and in human keratinocytes (Khan et al., 1992Khan I.U. Bickers D.R. Haqqi T.M. et al.Induction of CYPIAl mRNA in rat epidermis and cultured human epidermal keratinocytes by benz(a)anthracene and β-naphthoflavone.Drug Metab Dispos. 1992; 22: 620-624Google Scholar). In another study,Raza et al., 1992Raza H. Agarwal R. Bickers D.R. et al.Purification and molecular characterization of β-naphthoflavone inducible cytochrome P-450 from rat epidermis.J Invest Dermatol. 1992; 98: 233-240Abstract Full Text PDF PubMed Scopus (25) Google Scholar demonstrated that topically applied β-NF (40 μg per kg) to rats resulted in a significant induction of CYP1A1 expression and monooxygenase activity in epidermis.Stauber et al., 1995Stauber K.L. Laskin J.D. Yurkow E.J. et al.Flow cytometry reveals subpopulations of murine epidermal cells that are refractory to induction of cytochrome P-450 1A1 by β-naphthoflavone.J Pharmacol Exp Ther. 1995; 273: 967-976PubMed Google Scholar demonstrated that CYP1A1 expression also depends on the progression of cell differentiation. In this study, it was shown that topical application of β-NF, to mice, resulted in ∼87-fold enhancement in epidermal 7-ethoxyresorufin deethylase (EROD) activity per cell and a manifold increase in CYP1A1 expression in the epidermis. It was also found that the β-NF application leads to a CYP1A1 increase only in 40%–50% of the isolated epidermal cells. Moreover, the population of epidermal cells containing β-NF-induced elevated CYP1A1 expression was enriched in superbasal differentiated cells and also contained some basal cells. Similarly,Reiners et al., 1992Reiners J.J. Cantu A.R. Thai G. et al.Differential expression of basal and hydrocarbon induced cytochrome P-450 monooxygenase and quinone reductase activities in subpopulations of murine epidermal cells differing in their stages of differentiation.Drug Metab Dispos. 1992; 20: 360-366PubMed Google Scholar demonstrated the existence of a differential expression of both basal and inducible phase-I and phase-II metabolizing enzymes in the epidermis that was regulated as a function of the stage of epidermal differentiation. The expression and modulation of CYP1A1 is associated with the AHH activity in the skin (Lilienblum et al., 1985Lilienblum W. Irmscher G. Fusenig N. et al.Induction of UDP-glucuronosyltransferases in rat skin.Biochem Pharmacol. 1985; 35: 1517-1520Crossref Scopus (15) Google Scholar;Pham et al., 1989Pham M.A. Magdalou J. Totis M. et al.Characterization of distinct forms of cytochrome P-450, epoxide metabolizing enzymes and UDP-glucuronosyltransferases in rat skin.Biochem Pharmacol. 1989; 38: 2187-2194Crossref PubMed Scopus (48) Google Scholar;Gonzalez, 1995Gonzalez F.J. Role of cytochrome P450 1A1 in skin cancer.in: Mukhtar H. Skin Cancer: Mechanism and Human Relevance. CRC Press, Boca Raton, FL1995: 89-97Google Scholar), which is responsible for the metabolic activation of PAH such as BaP. The 7-ethoxycoumarin deethylase (ECOD) and the EROD activities are also catalyzed by CYP1A1 in the skin.Wattenberg and Leong, 1962Wattenberg L.W. Leong J.L. Histochemical studies of polycyclic hydrocarbon metabolizing systems.J Histochem Soc. 1962; 10: 659Google Scholar demonstrated that the application of 3-methylcholanthrene resulted in an enhanced cutaneous AHH activity in rats. Several other studies have also shown significant induction of AHH and related enzyme activities, i.e. ECOD and/or EROD in skin by the topical or systemic administration of a wide range of xenobiotics including PAH, tetrachlorodibenzo-p-dioxin, and Aroclor 1254. Studies have also shown that the topical application was the most effective of all modes of xenobiotics exposure in terms of the induction in the above-mentioned enzyme activities (Khan et al., 1989Khan W.A. Park S.S. Gelboin H.V. et al.Epidermal cytochrome P-450: Immunochemical characterization of isoform induced by topical application of 3-methylcholanthrene to neonatal rats.J Pharmacol Exp Ther. 1989; 249: 921-924PubMed Google Scholar;Raza and Mukhtar, 1993Raza H. Mukhtar H. Differences in inducibility of cytochrome P-450 1A1, monooxygenases and glutathione-S-transferases in cutaneous and extra-cutaneous tissues after topical and parenteral administration of β-naphthoflavone to rats.Int J Biochem. 1993; 10: 1511-1516Crossref Scopus (14) Google Scholar).Schlede and Conney, 1970Schlede E. Conney A.H. Induction of benzo(a)pyrene hydroxylase activity in rat skin.Life Sci. 1970; 9: 1295-1303Crossref Scopus (20) Google Scholar demonstrated that topically applied 3-methylcholanthene results in a 10-fold increase in cutaneous AHH activity in rats.Levin et al., 1972Levin W. Conney A.H. Alvares A.P. et al.Induction of benzo(a)pyrene hydroxylase in human skin.Science. 1972; 176: 419-420Crossref PubMed Scopus (83) Google Scholar andAlvares et al., 1973Alvares A.P. Kappas A. Levin W. et al.Inducibility of benzo(a)pyrene hydroxylase in human skin by polycyclic hydrocarbons.Clin Pharmacol Ther. 1973; 14: 30-40PubMed Google Scholar demonstrated the induction of BaP hydroxylase in human skin by PAH.Bickers et al., 1974Bickers D.R. Kappas A. Alvares A.P. Differences in inducibility of cutaneous and hepatic drug metabolizing enzymes and cytochrome P-450 by polychlorinated biphenyls and 1, 1, l-trichloro-2,2,-bis(p-chlorophenyl)ethane (DDT).J Pharmacol Exp Ther. 1974; 188: 300-309PubMed Google Scholar, Bickers et al., 1975Bickers D.R. Eiseman J. Kappas A. et al.Microscope immersion oils: Effects of skin application on cutaneous and hepatic drug metabolizing enzymes.Biochem Pharmacol. 1975; 24: 779-783Crossref PubMed Scopus (26) Google Scholar demonstrated that a commercial mixture of polychlorinated biphenyls, Aroclor 1254, or the microscope immersion oil containing these compounds, when applied topically, results in significant AHH induction in skin.Thompson and Slaga, 1976Thompson S. Slaga T.J. Mouse epidermal aryl hydrocarbon hydroxylase.J Invest Dermatol. 1976; 66: 108-111Crossref PubMed Scopus (69) Google Scholar demonstrated the induction of cutaneous AHH activity in the mouse by topical application of PAH. Weibel et al., 1971Weibel F.J. Leutz J.C. Diamond L. et al.Aryl hydrocarbon [benzo(a)pyrene] hydroxylase in microsomes from rat tissue: Differential inhibition and stimulation by benzoflavones and organic solvents.Arch Biochem Biophys. 1971; 144: 78-86Crossref PubMed Scopus (338) Google Scholar demonstrated that the topical application of benz(a)anthracene results in significant AHH induction in mouse skin. Later, it was found that the AHH activity in mouse skin possesses certain features analogous with the hepatic NADPH-dependent mixed function oxidase (Weibel et al., 1975Weibel F.J. Leutz J.C. Gelboin H.V. Aryl hydrocarbon (benzo(a)pyrene) hydroxylase: A mixed function oxygenase in mouse skin.J Invest Dermatol. 1975; 64: 184-189Crossref PubMed Scopus (47) Google Scholar).Briggs and Briggs, 1973Briggs M.M. Briggs M. Induction by topical corticosteroids of skin enzymes metabolizing carcinogenic hydrocarbons.Br J Dermatol. 1973; 88: 75-81Crossref PubMed Scopus (21) Google Scholar showed that the topical application of selected adrenocorticosteroids used in the therapy of certain dermatological disorders may induce AHH activity in mouse skin. These authors suggested that the inducible enzyme activity in skin may have a correlation with the therapeutic efficacy of adrenocorticosteroids in skin therapy.Mukhtar and Bickers, 1981Mukhtar H. Bickers D.R. Comparative activity of the mixed function oxidases, epoxide hydratase, and glutathione-S-transferase in liver and skin of the neonatal rat.Drug Metab Dispos. 1981; 9: 311-314PubMed Google Scholar demonstrated that the topical application of BaP or Aroclor 1254 results in the AHH induction in skin as well as other tissues. The rate of increase in the enzyme activity, however, was much greater in skin as compared with the other tissues (Mukhtar and Bickers, 1981Mukhtar H. Bickers D.R. Comparative activity of the mixed function oxidases, epoxide hydratase, and glutathione-S-transferase in liver and skin of the neonatal rat.Drug Metab Dispos. 1981; 9: 311-314PubMed Google Scholar). These studies established that even though the specific enzyme activities are much lower in the skin as compared with liver, they may make a major contribution in the overall metabolism of xenobiotics in the body. Several other reports from our group further demonstrated the induction of cutaneous AHH, ECOD, and EROD activities in animal models, by a number of agents generally used in the therapy of several skin conditions (Bickers et al., 1982Bickers D.R. Wroblewski D. Dutta-Choudhury T. et al.Induction of neonatal rat skin and liver hydrocarbon hydroxylase by coal tar and its constituents.J Invest Dermatol. 1982; 78: 227-229Crossref PubMed Scopus (23) Google Scholar;Mukhtar and Bickers, 1982Mukhtar H. Bickers D.R. Evidence that coal tar is a mixed inducer of microsomal drug metabolizing enzymes.Toxicol Lett. 1982; 11: 221-227Crossref PubMed Scopus (14) Google Scholar;Mukhtar et al., 1982Mukhtar H. Link C.M. Cherniack E. et al.Effect of topical application of defined constituents of coal tar on skin and liver aryl hydrocarbon hydroxylase and 7-ethoxycoumarin deethylase activities.Toxicol Appl Pharmacol. 1982; 64: 541-549Crossref PubMed Scopus (31) Google Scholar;Merk et al., 1989Merk H.F. Khan W.A. Khun C. et al.Effect of topical application of clotrimazole to rats on epidermal and hepatic monooxygenase activities and cytochrome P-450.Arch Dermatol Res. 1989; 281: 198-202Crossref PubMed Scopus (16) Google Scholar). In a recent study,Harris et al., 2002Harris I.R. Siefken W. Beck-Oldach K. et al.Comparison of activities dependent on glutathione S-transferase and cytochrome P-450 1A1 in cultured keratinocytes and reconstructed epidermal models.Skin Pharmacol Appl Skin Physiol. 2002; 5: 59-67Crossref Scopus (39) Google Scholar measured
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