Cytochrome P450: A Target for Drug Development for Skin Diseases

Department of Dermatology, University of Wisconsin, 1300 University Avenue, Madison, WI 53706, USA.
Journal of Investigative Dermatology (Impact Factor: 7.22). 10/2004; 123(3):417-25. DOI: 10.1111/j.0022-202X.2004.23307.x
Source: PubMed


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.

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    • "Such AhR signaling was found in almost all cells of the body, including skin (Das et al., 1986; Ahmad et al., 1996). The skin is the largest organ of the human body and represents the body's protective surface as the first and outermost contact site for environmental noxae (Ahmad and Mukhtar, 2004; Swanson, 2004; Merk et al., 2006; Oesch et al., 2007). In this regard, it is important to note that lipophilic chemicals, such as polycyclic aromatic hydrocarbons and polyhalogenated hydrocarbons, or physical stressors, such as UV radiation, may overcome the physical barrier of the skin. "
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    ABSTRACT: The skin reacts to environmental noxae by inducing cytochrome P450 (CYP)-catalyzed reactions via activation of the aryl hydrocarbon receptor (AhR). A drawback of this response is the generation of oxidative stress, which is especially dangerous for postreplicative cells such as dermal fibroblasts, in which damage may accumulate over time. Accordingly, in dermal fibroblasts, CYP1 expression is repressed and it has been proposed that this is due to the AhR repressor (AhRR), which is supposedly overexpressed in fibroblasts as compared with other skin cells. Here, we revisited this "AhRR hypothesis", which has been mainly based on ectopic overexpression studies and correlation analyses of high AhRR gene expression with CYP1A1 repression in certain cell types. In primary human skin fibroblasts (NHDFs) of 25 individuals, we found that (i) the AhRR was expressed only at moderate RNA copy numbers and that, against the common view, (ii) in some fibroblast strains, CYP1A1 mRNA expression could be induced by AhR activators. However, even the highest induction did not translate into measurable CYP1 enzyme activity, and neither basal expression nor mRNA inducibility correlated with AhRR expression. In addition, enhancement of CYP1A1 mRNA expression by trichostatin A, which inhibits AhRR-recruited histone deacetylases at the CYP1A1 promoter, failed to induce measurable CYP1 activity. Finally, AhRR-deficient ((-/-)) mouse embryonic fibroblasts were not induced to biologically relevant CYP1 enzyme activity despite impressive mRNA induction. These data clearly indicate that repressed CYP1 activity in NHDFs is not causally related to AhRR expression, which may serve a different, yet unknown, biological function.Journal of Investigative Dermatology advance online publication, 6 September 2012; doi:10.1038/jid.2012.259.
    Journal of Investigative Dermatology 09/2012; 133(1). DOI:10.1038/jid.2012.259 · 7.22 Impact Factor
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    • "The skin expresses all known phase I and II enzymes, such as cytochrome P450 enzymes, flavin-dependent monooxygenase, monoamine oxidase, alcohol dehydrogenase, aldehyde dehydrogenase, NADP(H): quinone oxidoreductase, glutathione S-transferase, and catechol-O-methyhransferase [14,48]. The xenobiotic-metabolizing enzymes are induced in response to xenobiotic exposure [49,50]. Moreover, endogenous bioactive and toxic substances, such as catecholamines and steroids [48-51], are also substrates of phase I and II enzymes. "
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    ABSTRACT: The body's total antioxidant capacity represents a sum of the antioxidant capacity of various tissues/organs. A decrease in the body's antioxidant capacity may induce oxidative stress and subsequent metabolic syndrome, a clustering of risk factors for type 2 diabetes and cardiovascular disease. The skin, the largest organ of the body, is one of the major components of the body's total antioxidant defense system, primarily through its xenobiotic/drug biotransformation system, reactive oxygen species-scavenging system, and sweat glands- and sebaceous glands-mediated excretion system. Notably, unlike other contributors, the skin contribution is variable, depending on lifestyles and ambient temperature or seasonal variations. Emerging evidence suggests that decreased skin's antioxidant and excretory functions (e.g., due to sedentary lifestyles and low ambient temperature) may increase the risk for metabolic syndrome. This review focuses on the relationship between the variability of skin-mediated detoxification and elimination of exogenous and endogenous toxic substances and the development of metabolic syndrome. The potential role of sebum secretion in lipid and cholesterol homeostasis and its impact on metabolic syndrome, and the association between skin disorders (acanthosis nigricans, acne, and burn) and metabolic syndrome are also discussed.
    Diabetology and Metabolic Syndrome 04/2012; 4(1):15. DOI:10.1186/1758-5996-4-15 · 2.17 Impact Factor
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    • "(Hogg 1992), the biosynthesis of antibiotics like erythromycin by Hutchison and co-workers (Andersen et al. 1993; Shafiee and Hutchinson 1988), glycopeptide antibiotics (Bischoff et al. 2005), chemotherapeutic drugs (Jennewein and Croteau 2001; Jennewein et al. 2001) and new anticancer drugs (Jennewein et al. 2005). Also, CYPs have been used as drug targets (Brodie 1994) in the development of drugs for skin diseases (Ahmad and Mukhtar 2004), in the process of bioremediation and biodegradation (Guengerich 1995a; Jones et al. 2001; Kellner et al. 1997) and for the production of chemicals with commercial applications (Guengerich 2001). "
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    ABSTRACT: DNA family shuffling is a relatively new method of directed evolution used to create novel enzymes in order to improve their existing properties or to develop new features. This method of evolution in vitro has one basic requirement: a high similarity of initial parental sequences. Cytochrome P450 enzymes are relatively well conserved in their amino acid sequences. Members of the same family can have more than 40% of sequence identity at the protein level and are therefore good candidates for DNA family shuffling. These xenobiotic-metabolising enzymes have an ability to metabolise a wide range of chemicals and produce a variety of products including blue pigments such as indigo. By applying the specifically designed DNA family shuffling approach, catalytic properties of cytochrome P450 enzymes were further extended in the chimeric progeny to include a new range of blue colour formations. This mini-review evokes the possibility of exploiting directed evolution of cytochrome P450s and the novel enzymes created by DNA family shuffling for the production of new dyes.
    Applied Microbiology and Biotechnology 02/2009; 82(2):203-10. DOI:10.1007/s00253-008-1812-8 · 3.34 Impact Factor
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