title: Toxicity of Trp-P-2 to cultured human and rat keratinocytes.
abstract: Keratinocytes cultured from human and rat epidermis exhibited strongly divergent sensitivities to toxicity from the heterocyclic amine food mutagen Trp-P-2. To find a biochemical basis for this difference, the cultured cells were compared in their expression of phase 1 and 2 biotransformation activities, mutagenic activation and macromolecular adducts. The human and early passage rat cells expressed similar levels of ethoxyresorufin O-deethylase and N-acetyl transferase activities, their microsomes were similarly active in inducing bacterial mutagenesis when incubated with Trp-P-2, and the keratinocytes accumulated similar levels of DNA adducts over a 4-day treatment period. However, the human cells expressed an order of magnitude higher cytosolic glutathione S-transferase activity than the rat cells, likely providing enhanced protection. Late passage rat epidermal cells were insensitive to Trp-P-2 toxicity, attributable to their rapid loss of measured cytochrome P450 activity. Rat esophageal and fore-stomach epithelial cells resembled late passage rat epidermal cells in their lack of sensitivity to Trp-P-2 toxicity and lack of P450 activity. Human esophageal epithelial cells expressed substantial P450 activity but, in contrast to human epidermal cells, were sensitive to Trp-P-2 toxicity. Thus keratinocytes provide a valuable system in which to examine the basis for species- and tissue-specific differences in toxicity from this carcinogenic heterocyclic amine.
authors.affiliation: Department of Environmental Toxicology, One Shields Avenue, University of California, Davis, CA 95616-8588, USA.
authors.forename: H S
authors.initials: HS
authors.lastname: Chun
authors.forename: P A
authors.initials: PA
authors.lastname: Kuzmicky
authors.forename: N Y
authors.initials: NY
authors.lastname: Kado
authors.forename: R H
authors.initials: RH
authors.lastname: Rice
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000378:metabolism; D001711:Biotransformation; D002243:Carbolines / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D018736:DNA Adducts / Q000096:biosynthesis; D000078404:Epidermal Cells; D004947:Esophagus / Q000166:cytology; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D009152:Mutagenicity Tests; D009153:Mutagens / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
chemical_list: D002243:Carbolines; D018736:DNA Adducts; D009153:Mutagens; D000072317:Polychlorinated Dibenzodioxins; D019363:Cytochrome P-450 CYP1A1; D001191:Arylamine N-Acetyltransferase; C019132:3-amino-1,4-dimethyl-5H-pyrido(4,3-b)indole