Studies of the expression of the cytochrome P450IA, P450IIB, and P450IIC gene family in extrahepatic and hepatic tissues.

Friedberg, Thomas; Siegert, Peter; Grassow, Markus A.; Bartłomowicz, B; Oesch, Franz

doi:10.1289/ehp.908867

Cited by 13 publications

(2 citation statements)

References 11 publications

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“…A novel CYP, termed CYP2B12, was found not to be expressed in the liver but in the preputial gland (Friedberg et al 1990 , 1992 ) and then discovered to be a keratinocyte-specific 11,12- and 8,9-epoxygenase of arachidonic acid having a high, constitutive expression in the sebaceous glands, being expressed exclusively in a subset of differentiated keratinocytes called sebocytes. Its expression coincides with the morphological appearance of sebaceous glands in the neonatal rat (Keeney et al 1998a , b ).…”

Section: Xenobiotic-metabolizing Enzymes In the Rat Skinmentioning

confidence: 99%

Xenobiotic-metabolizing enzymes in the skin of rat, mouse, pig, guinea pig, man, and in human skin models

Oesch¹,

Fabian

Guth

et al. 2014

Arch Toxicol

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The exposure of the skin to medical drugs, skin care products, cosmetics, and other chemicals renders information on xenobiotic-metabolizing enzymes (XME) in the skin highly interesting. Since the use of freshly excised human skin for experimental investigations meets with ethical and practical limitations, information on XME in models comes in the focus including non-human mammalian species and in vitro skin models. This review attempts to summarize the information available in the open scientific literature on XME in the skin of human, rat, mouse, guinea pig, and pig as well as human primary skin cells, human cell lines, and reconstructed human skin models. The most salient outcome is that much more research on cutaneous XME is needed for solid metabolism-dependent efficacy and safety predictions, and the cutaneous metabolism comparisons have to be viewed with caution. Keeping this fully in mind at least with respect to some cutaneous XME, some models may tentatively be considered to approximate reasonable closeness to human skin. For dermal absorption and for skin irritation among many contributing XME, esterase activity is of special importance, which in pig skin, some human cell lines, and reconstructed skin models appears reasonably close to human skin. With respect to genotoxicity and sensitization, activating XME are not yet judgeable, but reactive metabolite-reducing XME in primary human keratinocytes and several reconstructed human skin models appear reasonably close to human skin. For a more detailed delineation and discussion of the severe limitations see the “Overview and Conclusions” section in the end of this review.

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Section: Xenobiotic-metabolizing Enzymes In the Rat Skinmentioning

confidence: 99%

Xenobiotic-metabolizing enzymes in the skin of rat, mouse, pig, guinea pig, man, and in human skin models

Oesch¹,

Fabian

Guth

et al. 2014

Arch Toxicol

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“…A novel CYP, CYP2B12, was observed in the preputial gland, but not in the liver (Friedberg et al 1990 , 1992 ). This CYP turned out to be an arachidonic acid 8,9- and 11,12-epoxygenase present exclusively in sebocytes (Keeney et al 1998 ).…”

Section: Xenobiotica-metabolizing Enzymes In the Rat Skinmentioning

confidence: 99%

Xenobiotica-metabolizing enzymes in the skin of rat, mouse, pig, guinea pig, man, and in human skin models

2018

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Studies on the metabolic fate of medical drugs, skin care products, cosmetics and other chemicals intentionally or accidently applied to the human skin have become increasingly important in order to ascertain pharmacological effectiveness and to avoid toxicities. The use of freshly excised human skin for experimental investigations meets with ethical and practical limitations. Hence information on xenobiotic-metabolizing enzymes (XME) in the experimental systems available for pertinent studies compared with native human skin has become crucial. This review collects available information of which—taken with great caution because of the still very limited data—the most salient points are: in the skin of all animal species and skin-derived in vitro systems considered in this review cytochrome P450 (CYP)-dependent monooxygenase activities (largely responsible for initiating xenobiotica metabolism in the organ which provides most of the xenobiotica metabolism of the mammalian organism, the liver) are very low to undetectable. Quite likely other oxidative enzymes [e.g. flavin monooxygenase, COX (cooxidation by prostaglandin synthase)] will turn out to be much more important for the oxidative xenobiotic metabolism in the skin. Moreover, conjugating enzyme activities such as glutathione transferases and glucuronosyltransferases are much higher than the oxidative CYP activities. Since these conjugating enzymes are predominantly detoxifying, the skin appears to be predominantly protected against CYP-generated reactive metabolites. The following recommendations for the use of experimental animal species or human skin in vitro models may tentatively be derived from the information available to date: for dermal absorption and for skin irritation esterase activity is of special importance which in pig skin, some human cell lines and reconstructed skin models appears reasonably close to native human skin. With respect to genotoxicity and sensitization reactive-metabolite-reducing XME in primary human keratinocytes and several reconstructed human skin models appear reasonably close to human skin. For a more detailed delineation and discussion of the severe limitations see the Conclusions section in the end of this review.

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Hormonal Regulation of Liver Cytochrome P450 Enzymes

Waxman

Chang

Cytochrome P450

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Abbreviations CIScytokine-inducible SH2-containing protein CYP cytochrome P450 GH growth hormone GHR GH receptor HNF hepatocyte nuclear factor 3MC 3-methylcholanthrene MSG monosodium glutamate SOCS suppressor of cytokine signaling protein STAT signal transducer and activator of transcription IntroductionInterindividual differences in response to drugs are well documented [1][2][3] Various factors, including sex [4][5][6][7], contribute to the variability in drug response As first reported in the 1930s, female rats respond to a lower dosage of amobarbital [8] and experience a longer duration of action of this barbiturate [9] than male rats In the 1960s and 1970s, sex differences in hepatic drug metabolism were identified using liver microsomes assayed in vitro using prototypic phase I cytochrome P450 (CYP) drug substrates, such as ethylmorphine, benzo[a]pyrene, and hexobarbital (Fig 111) [10-13] These studies showed that the sex dependence of hepatic P450 metabolism is most striking in the rat, where sex differences in metabolic rates can be fivefold or more with some drug substrates, even though the total liver P450 content is only ~ 20 % higher in males compared to females (Fig 111) Research carried out in the 1980s resolved this discrepancy with the discovery that a subset of the multiple drug-metabolizing P450 enzymes in rat liver [14, 15] is expressed in a highly sex-dependent manner [16] Many P450 enzymes in the CYP gene superfamily are active in foreign compound metabolism, in particular, genes in families CYP1, CYP2, and CYP3 These three families encompass 23 CYP genes (human), 50 CYP genes (rat), and 61 CYP genes (mouse) [17], and collectively carry out essentially all of the phase I CYP metabolic reactions in mammalian liver A subset of these hepatic P450s is expressed in a sex-dependent manner subject to endocrine control [18] The sex dependence of liver P450 enzyme expression has been widely studied at the gene (RNA) level in the rat and mouse models, but has also been reported for other species, including humans Human liver P450 metabolism is associated with significant male-female differences in the elimination pharmacokinetics of many drugs [4, 7, P R Ortiz de Montellano et al (eds), Cytochrome P450,

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Studies of the expression of the cytochrome P450IA, P450IIB, and P450IIC gene family in extrahepatic and hepatic tissues.

Cited by 13 publications

References 11 publications

Xenobiotic-metabolizing enzymes in the skin of rat, mouse, pig, guinea pig, man, and in human skin models

Xenobiotic-metabolizing enzymes in the skin of rat, mouse, pig, guinea pig, man, and in human skin models

Xenobiotica-metabolizing enzymes in the skin of rat, mouse, pig, guinea pig, man, and in human skin models

Hormonal Regulation of Liver Cytochrome P450 Enzymes

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