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Faculty of Pharmacy [P. M. K., P. G. W.] and Department of Pharmacology [P. G. W.], University of Toronto, Toronto, Ontario, Canada M5S 2S2
UDP-glucuronosyltransferases (UGTs) catalyze the glucuronidation and elimination of putative tobacco carcinogens such as benzo[a]pyrene (B[a]P) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which may reduce competing bioactivation and toxicity. B[a]P-initiated cytotoxicity and micronucleus formation, believed to reflect carcinogenic initiation, are enhanced in UGT-deficient rat fibroblasts, and UGTs may provide similar genoprotection against NNK. Using skin fibroblasts from wild-type UGT-normal (+/+) and congenic heterozygous (+/j) and homozygous (j/j) UGT-deficient rats, this study evaluated NNK in relation to B[a]P with respect to the mechanism of genotoxicity, evidenced by micro-nucleus formation, and genoprotection by UGTs. Molecular mechanisms were determined by changes in B[a]P- and NNK-initiated micronucleus formation when cells were incubated with the antioxidative enzyme superoxide dismutase (1680 IU/ml), inhibitors of cytochrome P450 (1 mM 1-aminobenzotriazole) and peroxidases (1-aminobenzotriazole; 40 µM eicosatetraynoic acid), and inducers of CYP1A1/2(10 mM 2,3,7,8-tetrachlorodibenzo-p-dioxin) and peroxidases [2,3,7,8-tetrachlorodibezo-p-dioxin; 0.625 ng/ml (0.0367 nM) interleukin 1
; 1 µM 12-O-tetradecanoylphorbol-13-acetate]. In +/+ fibroblasts, NNK and B[a]P initiated concentration-dependent, respective maximum 2.7-fold and 1.7-fold increases over DMSO controls in micronucleus formation (P < 0.05), with 10 µM NNK being 2.4-fold more genotoxic than B[a]P (P < 0.05). In both +/j and j/j UGT-deficient cells, micronuclei initiated by NNK and B[a]P each were over 2-fold higher than that in +/+ UGT normal cells (P < 0.05). Both NNK- and B[a]P-initiated micronuclei were decreased by superoxide dismutase and cytochrome P450/peroxidase inhibitors, while only that initiated by B[a]P was enhanced, up to 2.4-fold, by inducers, of which only interleukin 1a was effective in all UGT phenotypes (P < 0.05). These results provide the first evidence that: (a) UGTs may be genoprotective for NNK, with even heterozygous UGT deficiencies being toxicologically critical; and (b) peroxidase-catalyzed bioactivation, reactive oxygen species, and molecular target oxidation may contribute differentially to the genotoxicity of both NNK and B[a]P.
1 Supported by a grant from the Medical Research Council of Canada. Presented at the Annual Meeting of the Society of Toxicology, Anaheim, CA, March 1996 (Toxicologist, 16: 1188, 1996).
2 To whom requests for reprints should be addressed. Phone: (416) 978-3221; Fax: (416) 978-8511.
Received 10/ 9/95. Accepted 1/30/96.
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