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Species Specificity in the Metabolism of N-Nitrosobis(2-oxopropyl)amine and N-Nitroso(2-hydroxypropyl)(2-oxopropyl)amine to Mutagens by Isolated Rat and Hamster Hepatocytes¹

Department of Pathology, Northwestern University Medical School, Chicago, Illinois 60611

The metabolic activation of the carcinogens N-nitrosobis(2-oxopropyl)amine (BOP) and N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP) by Fischer rat and Syrian hamster hepatocytes was investigated in order to determine the existence of species differences in the induction of cell mutation. The conversion of BOP and HPOP into forms mutagenic to V79 cells was studied by using the hepatocyte-mediated mutagenicity assay. Mutations at the hypoxanthine:guanine phosphoribosyltransferase locus and the Na-K-ATPase locus were scored by the induction of 6-thioguanine resistance (TG^r) or ouabain resistance (Oua^r), respectively. Hepatocytes of both species were capable of converting BOP and HPOP to mutagens for V79 cells in a dose-dependent manner. Metabolism of BOP by rat hepatocytes resulted in higher mutation frequencies than that by hamster hepatocytes. At a BOP concentration of 240 µM, rat hepatocyte metabolism yielded 90.7 TG^r mutants and 19.5 Oua^r mutants per 10⁵ V79 cells. At the same concentration, hamster hepatocyte metabolism of BOP yielded 54.1 TG^r mutants and 13.0 Oua^r mutants per 10⁵ V79 cells. These results did not correlate with the known carcinogenic potency of BOP in the hamster as compared to the rat. Hamster hepatocytes carried out the catabolism of BOP to CO₂ at faster rates than rat hepatocytes; therefore, the species difference in mutagenic activation was not due to a defect in BOP uptake or metabolism by hamster hepatocytes. In contrast, metabolism of HPOP by hamster hepatocytes resulted in significantly higher mutation frequencies than that by rat hepatocytes. At an HPOP concentration of 240 µM, hamster hepatocyte metabolism yielded 83.5 TG^r mutants per 10⁵ V79 cells; rat hepatocyte metabolism yielded only 19.8 TG^r mutants per 10⁵ V79 cells. This species difference in mutagenic activation correlated well with the known potency of HPOP as a carcinogen for the hamster as compared to the rat. Since hamster pancreatic cells and subcellular fractions are known to have very limited capacity to perform the metabolic activation of HPOP, the results of this study imply that liver metabolism plays an important role in the conversion of HPOP to an agent(s) which subsequently affects the hamster pancreas. The mutagenic potency of BOP versus HPOP was compared after metabolism by hepatocytes from both species. Following their metabolism by hamster hepatocytes, the two compounds were nearly equivalent in mutagenic potency. After metabolism by rat hepatocytes, BOP was a significantly more potent mutagen than HPOP. This result was not consistent with the concept that cell mutation induced by BOP requires its conversion to HPOP and suggests that rat liver may convert BOP to a mutagen by another pathway(s) independent from its enzymatic reduction to HPOP.

¹ This work was supported by the Edith Patterson and Marie A. Fleming Cancer Research Funds (Northwestern University) and National Cancer Institute Grants CA 34051 and CA 16954.

² To whom requests for reprints should be addressed.

Received 2/24/87. Revised 6/16/87. Accepted 6/18/87.