Metabolic and redox barriers in the skin exposed to drugs and xenobiotics

ABSTRACT

Introduction: Growing exposure of human skin to environmental and occupational hazards, to numerous skin care/beauty products, and to topical drugs led to a biomedical concern regarding sustainability of cutaneous chemical defence that is essential for protection against intoxication. Since skin is the largest extra-hepatic drug/xenobiotic metabolising organ where redox-dependent metabolic pathways prevail, in this review, publications on metabolic processes leading to redox imbalance (oxidative stress) and its autocrine/endocrine impact to cutaneous drug/xenobiotic metabolism were scrutinised.

Areas covered: Chemical and photo-chemical skin barriers contain metabolic and redox compartments: their protective and homeostatic functions. The review will examine the striking similarity of adaptive responses to exogenous chemical/photo-chemical stressors and endogenous toxins in cutaneous metabolic and redox system; the role(s) of xenobiotics/drugs and phase II enzymes in the endogenous antioxidant defence and maintenance of redox balance; redox regulation of interactions between metabolic and inflammatory responses in skin cells; skin diseases sharing metabolic and redox problems (contact dermatitis, lupus erythematosus, and vitiligo)

Expert opinion: Due to exceptional the redox dependence of cutaneous metabolic pathways and interaction of redox active metabolites/exogenous antioxidants with drug/xenobiotic metabolism, metabolic tests of topical xenobiotics/drugs should be combined with appropriate redox analyses and performed on 3D human skin models.

KEYWORDS:

• AhR
• contact dermatitis
• GST
• Nrf2
• photo-chemical barrier
• redox signalling
• skin antioxidants
• skin xenobiotic/drug metabolising enzymes
• vitiligo

Article highlights.

• Skin is a universal innate defense of the organism against biotic and abiotic stresses. Four major lines of protection from xenobiotics/drugs are constitutively expressed: metabolic, redox, photochemical and immune barriers.

• All protective mechanisms in the skin are interconnected and regulated by redox-dependent processes.

• All four adaptive/protective barriers of the skin are induced-upon-exposure by similar molecular pathways trans-activated by transcription factors (Nrf2 and AhR).

• Inherited or acquired defects in one or several protective skin systems may lead to disturbances in the others, alter their interactions and ultimately lead to the development of distinct chronic skin pathologies.

• Metabolic tests of topically applied drugs/chemicals should be carried out on 3D human skin constructs.

• For a better prediction of toxicity or/and therapeutic efficacy, appropriate redox analyses could be performed in parallel on the same skin equivalents or their co-cultures with immune cells.

Declaration of Interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.