title: Elucidation of xenobiotic metabolism pathways in human skin and human skin models by proteomic profiling.
abstract: BACKGROUND
  Human skin has the capacity to metabolise foreign chemicals (xenobiotics), but knowledge of the various enzymes involved is incomplete. A broad-based unbiased proteomics approach was used to describe the profile of xenobiotic metabolising enzymes present in human skin and hence indicate principal routes of metabolism of xenobiotic compounds. Several in vitro models of human skin have been developed for the purpose of safety assessment of chemicals. The suitability of these epidermal models for studies involving biotransformation was assessed by comparing their profiles of xenobiotic metabolising enzymes with those of human skin.
  
  
  RESULTS
  Label-free proteomic analysis of whole human skin (10 donors) was applied and analysed using custom-built PROTSIFT software. The results showed the presence of enzymes with a capacity for the metabolism of alcohols through dehydrogenation, aldehydes through dehydrogenation and oxidation, amines through oxidation, carbonyls through reduction, epoxides and carboxylesters through hydrolysis and, of many compounds, by conjugation to glutathione. Whereas protein levels of these enzymes in skin were mostly just 4-10 fold lower than those in liver and sufficient to support metabolism, the levels of cytochrome P450 enzymes were at least 300-fold lower indicating they play no significant role. Four epidermal models of human skin had profiles very similar to one another and these overlapped substantially with that of whole skin.
  
  
  CONCLUSIONS
  The proteomics profiling approach was successful in producing a comprehensive analysis of the biotransformation characteristics of whole human skin and various in vitro skin models. The results show that skin contains a range of defined enzymes capable of metabolising different classes of chemicals. The degree of similarity of the profiles of the in vitro models indicates their suitability for epidermal toxicity testing. Overall, these results provide a rational basis for explaining the fate of xenobiotics in skin and will aid chemical safety testing programmes.
authors: Centre for Pharmacology and Therapeutics, Division of Experimental Medicine, Imperial College London, London, United Kingdom.
authors: Sven
authors: S
authors: van Eijl
authors: Zheying
authors: Z
authors: Zhu
authors: John
authors: J
authors: Cupitt
authors: Magdalena
authors: M
authors: Gierula
authors: Christine
authors: C
authors: Götz
authors: Ellen
authors: E
authors: Fritsche
authors: Robert J
authors: RJ
authors: Edwards
mesh_terms: D000328:Adult; D002460:Cell Line; D020405:Dermis / Q000033:anatomy & histology / Q000201:enzymology / Q000378:metabolism*; D004817:Epidermis / Q000033:anatomy & histology / Q000201:enzymology / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D053858:Metabolic Networks and Pathways; D008953:Models, Anatomic; D040901:Proteomics; D015262:Xenobiotics / Q000378:metabolism*
chemical_list: D015262:Xenobiotics