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

Abstract

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.

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

“…It has been shown that cutaneous biotransformation can inactivate toxic agents; however, at the same time, biotransformation may also contribute to sensitization and genotoxicity. Comprehensive investigations into the expression and functionality of enzymes involved in cutaneous biotransformation of xenobiotics in human skin ex vivo as well as in reconstructed tissue models are ongoing, and knowledge continues to improve (Gotz et al, 2012;Huh et al, 2010;Oesch et al, 2014). Pre-validation studies have in fact been conducted with HSEs to address genotoxicity (Brinkmann et al, 2013;Fautz et al, 2013) and skin metabolism (Schafer-Korting et al, 2006).…”

“…It has, however, to be noted that rat skin is more permeable than human skin (van Ravenzwaay and Leibold, 2004), and that skin metabolism differs between human and rat species. Thus, results obtained with rat models should be interpreted with care (Bartek et al, 1972;Jung and Maibach, 2015;Oesch et al, 2014). However, a triple pack using human in vitro data corrected by rat in vivo and in vitro data is an accepted refinement option for human risk assessment in the EU.…”

Highlight report: xenobiotic-metabolizing enzymes in skin models

“…Recently, Franz Oesch and colleagues have published a comprehensive review about the xenobiotic-metabolizing activity in skin of rat, mouse, pig, guinea pig, man, and human skin models (Oesch et al 2014). Since the skin is constantly exposed to different xenobiotics, its xenobiotic-metabolizing activity is of high relevance.…”

“…The use of human skin is limited for ethical and practical reasons. Therefore, non-human skin and in vitro skin models are frequently applied (Oesch et al 2014). The authors give a comprehensive overview over possibilities and limitations of the most frequently applied in vitro systems used in skin toxicology.…”

Highlight report: epoxide hydrolases—protection from reactive compounds and risk of cardiovascular disease

“…Drug metabolism represents a cutting edge topic in toxicology with a particular focus on toxification versus detoxification of xenobiotics (Oesch et al 2014;Rodriguez-Mateos et al 2014;Dohnal et al 2014), contribution of drug metabolism to oxidative stress (Xiao et al 2014;Møller et al 2014;Wu et al 2014), and regulation of metabolic activity (Juricek et al 2014;Bitter et al 2014;Lim et al 2014;Braeuning 2014). Moreover, recent research focuses on integrating metabolic pathways into mathematical models in order to predict the metabolic capacity of tissues and organs under physiological and disease conditions (Drasdo et al 2014a, b;Schliess et al 2014;Hoehme et al 2010).…”