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Synthesis and Mutagenicity of 4-(N-Butylnitrosamino)-4-hydroxybutyric Acid Lactone, a Possible Activated Metabolite of the Proximate Bladder Carcinogen N-Butyl-N-(3-carboxypropyl)nitrosamine¹

Tokyo Biochemical Research Institute, Takada 3-41-8, Toshima-ku, Tokyo 171, Japan, and Veterans Administration Hospital, Memphis, Tennessee 38104

4-(N-Butylnitrosamino)-4-hydroxybutyric acid lactone (BBAL) was synthesized as a possible intermediate produced by metabolic activation of a selective bladder carcinogen, N-butyl-N-(3-carboxypropyl)nitrosamine. BBAL was stable in neutral sodium phosphate buffer (ionic strength, 0.2), having a half-life of more than 30 hr at 25°. The mutagenic effects of BBAL were tested with the use of Salmonella typhimurium TA1535 and Escherichia coli B/rWP2-try^-, WP2-try^-hcr^-, and Sd4. The gene-damaging effects were assayed by repair tests with Bacillus subtilis H17 (rec⁺) and M45 (rec^-). BBAL showed potent effects in the mutation and repair tests on all the strains tested without activation. A possibility is suggested for the metabolic activation of N-butyl-N-(3-carboxypropyl)-nitrosamine to BBAL by -hydroxylation at the site of the 3-carboxypropyl chain followed by lactonization in target tissues prior to interaction with macromolecules to lead to carcinogenesis.

¹ Supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Education, Science and Culture, Japan, by the U.S.-Japan Cooperative Cancer Research Program from the Japan Society for the Promotion of Science and by USPHS Research Grant CA16765 from the National Cancer Institute through the National Bladder Cancer Project. Presented at the 36th Annual Meeting of the Japanese Cancer Association, October 1977, Tokyo (14).

² To whom requests for reprints should be addressed.

Received 5/29/79. Accepted 10/11/79.

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