Human skin absorption and metabolism of the contact allergens, cinnamic aldehyde, and cinnamic alcohol

trans-Cinnamaldehyde and trans-cinnamic alcohol have been commonly reported to cause allergic contact dermatitis (ACD) in humans. Cinnamaldehyde is a more potent skin sensitizer than cinnamic alcohol. It has been hypothesized that cinnamic alcohol is a "prohapten" that requires metabolic activation, presumably by oxidoreductase enzymes such as alcohol dehydrogenase (ADH) o r cytochrome P450 2E1 (CYP2E1), to the protein-reactive cinnamaldehyde (a h apten). In this study, the in vitro percutaneous absorption and metabolism of cinnamaldehyde and cinnamic alcohol (78 mu mol dose) has been examined u sing freshly excised, metabolically viable, full-thickness breast and abdom en skin from six female donors. Penetration rates and total cumulative reco veries of cinnamic compounds that were present in receptor fluid, extracted from within the skin, evaporated from the skin surface, or remained unabso rbed on the skin surface after 24 h were quantified by reversed-phase high- performance liquid chromatography. Biotransformation of cinnamaldehyde to b oth cinnamic alcohol and cinnamic acid was observed. Topically applied cinn amic alcohol was converted to cinnamaldehyde (found on the skin surface onl y) and cinnamic acid. To establish whether these biotransformations were en zymatic, experiments were performed in the absence and presence of varying concentrations (80-320 mu mol) of the ADH/CYP2E1 inhibitors pyrazole: or 4- methylpyrazole. The observation that pyrazole significantly reduced (p < 0. 05) the total penetration of cinnamic metabolites into receptor fluid, foll owing either cinnamaldehyde or cinnamic alcohol treatment, but did not sign ificantly affect parent chemical penetration, suggests that we are measurin g cutaneous metabolic products of ADH activity. The skin absorption and met abolism of cinnamaldehyde and cinnamic alcohol will play an important role in the manifestation of ACD following topical exposure to these compounds. (C) 2000 Academic Press.