Dietary Protein Concentration and the Metabolism of 1,2-Dimethylhydrazine by Mice
Kari, Frank Walter
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Permalink
https://hdl.handle.net/2142/77436
Description
Title
Dietary Protein Concentration and the Metabolism of 1,2-Dimethylhydrazine by Mice
Author(s)
Kari, Frank Walter
Issue Date
1981
Department of Study
Food Science
Discipline
Food Science
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Health Sciences, Nutrition
Language
eng
Abstract
Experiments were conducted to assess the effect of dietary protein concentration on the metabolism of 1,2-dimethylhydrazine (DMH) to mutagenic products by male B(,6)C(,3)F(,1) mice. Our data reveal that the host-mediated bacterial mutagen assay is a valid indicator of the host's ability to activate DMH and its principle metabolites to carcinogenic products. At concentrations ranging from 2.5 to 10 mM, DMH and azoxymethane (AOM) did not increase the mutation frequency of Salmonella typhimurium (Strain G-46) in vitro. Murine liver microsomes and cofactors caused a 40-fold increase in mutation frequency with dimethylnitrosamine (DMN) but not with DMH or AOM in vitro. Methylazoxymethanol (MAM) was mutagenic in vitro without activation by liver preparations. At doses ranging from 0.2 to 0.8 mmoles/kg B.W., the subcutaneous administration of DMH, AOM, and MAM elicited dose-dependent increases in mutation frequency in S. typhimurium in the peritoneal cavity. Corresponding ranges of activity (reversions/10('8) bacterial survivors) from these three chemicals were: 9 (+OR-) 3 to 37 (+OR-) 5; 20 (+OR-) 2 to 130 (+OR-) 16; and 19 (+OR-) 3 to 760 (+OR-) 112. Mice that were normal, ether anesthetized, sham operated, or partially hepatectomized yielded 380, 199, 224, and 4 reversions/10('8) survivors respectively. In time course studies employing subcutaneous or intraperitoneal injections of the text chemicals, host-mediated mutagenesis was increased by AOM in 20 min while DMH-induced activity required at least 1 hr. When {('14)C}-DMH was administered {('14)C}-azomethane was expired immediately, while ('14)CO(,2) followed at one hour. The conversion of DMH, AOM, and MAM to mutagens was studied in growing mice fed isocaloric, semipurified casein, sucrose:dextrin diets containing 2.5, 5, 10, 20, or 40% protein. Fourteen-day weight gains were 1 (+OR-) 1, 5 (+OR-) 1, 9 (+OR-) 2, 10 (+OR-) 2, 8 (+OR-) 1 g, respectively. Mutagen formation from DMH and MAM varied slightly with diet but from AOM was directly proportional to dietary protein concentration, and increased from 74 (+OR-) 8 revertants/10('8) survivors at 2.5% protein to 253 (+OR-) 130 at 40% (p < .01). The percent of {('14)C}-DMH expired as a promutagen by growing mice fed 2.5, 10, or 40% protein was 63 (+OR-) 4, 44 (+OR-) 3, and 38 (+OR-) 3. The metabolism of DMH to mutagenic endproducts by mice was rate-limited by the conversion of azomethane to AOM and at least partially carried out by the liver. Increasing protein intake increased the bioactivation of DMH, AOM, and MAM and 2.5% protein diets caused greater (p < .05) expiration of promutagens from DMH, thereby decreasing the body burden of retained carcinogen.
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