Cytochrome P-450 and Drug Development for Skin Diseases

Ahmad, Nihal; Agarwal, Rajesh; Mukhtar, Hasan

doi:10.1159/000211420

Cited by 16 publications

(6 citation statements)

References 32 publications

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“…Several studies have demonstrated the inducibility of CYP1A1 and related mono-oxygenase activities in human skin, and in hair follicles, following the exposure to PAHs, b-naphtoflavones and glucocorticoids. 27 Data obtained in the present study confirmed the constitutive expression of this CYP mRNA in preparations of human epidermal keratinocytes, and in the resulting cultured keratinocytes, even after UV irradiation. The same observation was made about CYP3A5.…”

Section: Discussionsupporting

confidence: 85%

Cytochrome P450 4A11 expression in human keratinocytes: effects of ultraviolet irradiation.

Marteau

Franchi

et al. 2001

Br J Dermatol

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Section: Discussionsupporting

confidence: 85%

Cytochrome P450 4A11 expression in human keratinocytes: effects of ultraviolet irradiation.

Marteau

Franchi

et al. 2001

Br J Dermatol

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“…Thereby, the AhRR is thought to form a negative feedback loop on the AhR gene battery, including its own transcription. Such AhR signaling was found in almost all cells of the body, including skin (Das et al, 1986;Ahmad et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Aryl Hydrocarbon Receptor Repressor (AhRR) Function Revisited: Repression of CYP1 Activity in Human Skin Fibroblasts Is Not Related to AhRR Expression

Tigges

Weighardt

Wolff

et al. 2013

Journal of Investigative Dermatology

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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.

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“…The role of PXR in the skin has been little investigated [213] even though the skin is an important xenobiotic metabolizing organ which expresses several PXR target genes [54,125,213,214,215]. Natural PXR ligands in the skin are not known, but could include progesterone and cholesterol, and their derivatives, bile acids, pregnanes and corticosterone [216,217,218,219,220,221].…”

Section: Xenobiotic Receptors and Atopic Dermatitismentioning

confidence: 99%

Xenobiotic Receptors and Their Mates in Atopic Dermatitis

Minzaghi¹,

Pavel²,

Dubrac³

2019

IJMS

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Atopic dermatitis (AD) is the most common inflammatory skin disease worldwide. It is a chronic, relapsing and pruritic skin disorder which results from epidermal barrier abnormalities and immune dysregulation, both modulated by environmental factors. AD is strongly associated with asthma and allergic rhinitis in the so-called ‘atopic march.’ Xenobiotic receptors and their mates are ligand-activated transcription factors expressed in the skin where they control cellular detoxification pathways. Moreover, they regulate the expression of genes in pathways involved in AD in epithelial cells and immune cells. Activation or overexpression of xenobiotic receptors in the skin can be deleterious or beneficial, depending on context, ligand and activation duration. Moreover, their impact on skin might be amplified by crosstalk among xenobiotic receptors and their mates. Because they are activated by a broad range of endogenous molecules, drugs and pollutants owing to their promiscuous ligand affinity, they have recently crystalized the attention of researchers, including in dermatology and especially in the AD field. This review examines the putative roles of these receptors in AD by critically evaluating the conditions under which the proteins and their ligands have been studied. This information should provide new insights into AD pathogenesis and ways to develop new therapeutic interventions.

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Cytochrome P-450 and Drug Development for Skin Diseases

Cited by 16 publications

References 32 publications

Cytochrome P450 4A11 expression in human keratinocytes: effects of ultraviolet irradiation.

Cytochrome P450 4A11 expression in human keratinocytes: effects of ultraviolet irradiation.

Aryl Hydrocarbon Receptor Repressor (AhRR) Function Revisited: Repression of CYP1 Activity in Human Skin Fibroblasts Is Not Related to AhRR Expression

Xenobiotic Receptors and Their Mates in Atopic Dermatitis

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