Metabolism of xenobiotics during percutaneous penetration: Role of absorption rate and cutaneous enzyme activity

Abstract

The role of absorption rate and enzyme activity on cutaneous metabolism of topically applied xenobiotics was assessed by determining the simultaneous percutaneous penetration/metabolism of benzo[ a]pyrene (B[ a]P) and 7-ethoxycoumarin (7-EC) in intact, metabolically viable skin of Sencar mice, hairless guinea pigs, and humans. In addition, specific activities of aryl hydrocarbon hydroxylase (AHH) and ethoxycoumarin deethylase (ECDE) were determined in cutaneous microsomal fractions. Both compounds were readily absorbed but only minimally metabolized. Sencar mouse and hairless guinea pig skin absorbed 55–60% of the applied B[ a]P dose and metabolized only 6 and 3%, respectively, of that absorbed. Human skin absorbed 31% of the applied dose and B[ a]P metabolism was not detectable. All three species absorbed 60–80% of the applied 7-EC dose. Sencar mouse and hairless guinea pig skin metabolized 1.3 and 1.2% of the absorbed dose, respectively, and human skin metabolized only 0.05%. When 7-EC absorption was increased to the maximum possible rate, its metabolism by Sencar mouse and hairless guinea pig skin was also substantially increased. In human skin, a much smaller increase in 7-EC absorption rate was possible and no increase in 7-EC metabolism occurred. Thus relatively slower absorption of 7-EC and B[ a]P by human skin may limit cutaneous metabolism of these penetrating compounds. Specific activities of AHH and ECDE were significantly lower in human skin than in Sencar mouse and hairless guinea pig skin, suggesting that low enzyme activity contributes as well to a low rate of metabolism by human skin compared to other species. Thus absorption rate and cutaneous enzyme activity are interrelated determinants of the extent of cutaneous metabolism of B[ a]P and 7-EC occurring during their percutaneous penetration, and slow absorption and low enzyme activity limit cutaneous metabolism of B[ a]P and 7-EC in human skin in particular.