Polycyclic aromatic hydrocarbon toxicity and induction of metabolism in cultivated esophageal and epidermal keratinocytes.
Serially cultivated keratinocytes of human and rat epidermis and esophagus were compared with respect to their sensitivity to toxic effects of 3-methylcholanthrene and ability to metabolize benzo(a)pyrene. 3-Methylcholanthrene was highly toxic to the human keratinocytes and to early-passage rat epidermal keratinocytes, as evidenced by markedly reduced growth upon continuous exposure or reduced colony-forming ability after 1-day exposure to concentrations of 0.4 to 40 microM in the culture medium. Rat esophageal and late-passage rat epidermal cells appeared insensitive to 3-methylcholanthrene by these criteria. All the cell types except late-passage rat epidermal cells metabolized benzo(a)pyrene at comparable rates, and expressed aryl hydrocarbon hydroxylase maximally inducible by similar concentrations of 3-methylcholanthrene. Biotransformation in the human cells was greatly inhibited by alpha-naphthoflavone, a specific inhibitor of aryl hydrocarbon hydroxylase. The lack of toxicity of 3-methylcholanthrene toward late-passage rat epidermal cells can be attributed to the low constitutive rate of biotransformation these cells exhibit. The insensitivity of rat esophageal cells despite substantial metabolic activity reflects the importance of intrinsic differences among keratinocytes derived from different epithelia and species in determining toxic response. Human cervical and monkey esophageal keratinocyte cultures also actively metabolized benzo(a)pyrene, illustrating further the utility of the culture system for exploring differences among species and epithelial cell types.
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors; D001564:Benzo(a)pyrene; D001580:Benzopyrenes / Q000378:metabolism; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism*; D004947:Esophagus / Q000166:cytology / Q000378:metabolism*; D007633:Keratins; D008748:Methylcholanthrene / Q000378:metabolism; D051379:Mice; D011083:Polycyclic Compounds / Q000378:metabolism / Q000633:toxicity*
D001580:Benzopyrenes; D011083:Polycyclic Compounds; D001564:Benzo(a)pyrene; D008748:Methylcholanthrene; D007633:Keratins; D001189:Aryl Hydrocarbon Hydroxylases