Chemico-Biological Interactions 127 (2000) 237 – 253 Toxicity of Trp-P-2 to cultured human and rat keratinocytes Hyang-Sook Chun 1 , Paul A. Kuzmicky, Norman Y. Kado, Robert H. Rice * Department of Enironmental Toxicology, One Shields Aenue, Uniersity of California, Dais, CA 95616 -8588, USA Received 14 February 2000; received in revised form 22 May 2000; accepted 1 June 2000 Abstract Keratinocytes cultured from human and rat epidermis exhibited strongly divergent sensi- tivities 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 epider- mal 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 www.elsevier.com/locate/chembiont Abbreiations: EROD, ethoxyresorufin-O-deethylase; hEp, human epidermal cells; hEs, human esophageal epithelial cells; NAT, N-acetyl transferase; rEp, rat epidermal cells; rEs, rat esophageal epithelial cells; rFst, rat fore-stomach epithelial cells; SIK, spontaneously immortalized keratinocytes; TCDD, 2,3,7,8-tetrachlorodibenzo-P-dioxin; Trp-P-1, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b ]indole; Trp-P-2, 3-amino-1-methyl-5H-pyrido[4,3-b ]indole. * Corresponding author. Tel.: +1-530-7525176; fax: +1-530-7523394. E-mail address: rhrice@ucdavis.edu (R.H. Rice). 1 Present address: Korea Food Research Institute, San 46-1, Songnam-si, 463-420, South Korea. 0009-2797/00/$ - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S0009-2797(00)00182-4