| The influence of purified vitamin A and its analogues (retinoids) and stored vitamin A in mouse liver on cancer initiation was studied. The test systems used are assays of the Salmonella mutagenicity, DNA binding, sister chromatid exchanges (SCE) and chromosome aberrations (CA) in V79 cells, and SCE in mice. Vitamin A alcohol (Rol) inhibited the mutagenicity of precarcinogens aflatoxin B1 (AFB), cyclophosphamide (CPP), and 3-methylcholanthrene (MCA) activated by the rat liver S9 cytochrome P-450 enzymes. Rol did not inhibit that of benzo(a)pyrene (BP), benz(a)anthracene (BA), 9,10-dimethyl-1,2-benz(a)anthracene (DMBA), and the direct carcinogen mitomycin C (MMC). Vitamin A acid (RA) and vitamin A acetate (RAc) inhibited the mutagenicity of AFB, but not that of BP. A known inhibitor of certain P-450 isozymes, 7,8-benzoflavone, inhibited both AFB- and BP-induced mutations.; Rol inhibited AFB- and CPP-induced SCE. It did not inhibit that induced by BP, DMBA, BA, MCA, and direct carcinogens MMC, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), and ethyl methane sulfonate (EMS). Rol also inhibited AFB- and CPP-induced CA, but no such inhibition was observed in BP- and DMBA-induced CA. At a lower S9 concentration, physiological serum levels of Rol were sufficient for reducing of AFB- and CPP-induced SCE.; Retinoids (Rol, RA, and RAc) were not mutagenic to Salmonella tester strains and V79 cells, but were toxic to V79 and a human lymphoid cell line. The toxicity of retinoids was greatly reduced by S9 or its high speed-supernatant. This detoxification was due to the binding of retinoids to specific binding proteins present in liver S9.; Non-induced liver S9 prepared from mice with a low average content of liver vitamin A was more potent in activating AFB than was S9 from mice containing a high average level of vitamin A in the Salmonella mutagenicity assay. Liver stored vitamin A had no inhibitory effect on the mutagenicity of BP. Liver vitamin A inhibited the binding of ('3)H -AFB to purified DNA. A new 5-bromodeoxyuridine-agar injection method for in vivo SCE study was developed. AFB was activated more effectively into SCE-inducing metabolites in mice with low average liver vitamin A level than in mice with high vitamin A level. The metabolic activation of CPP or BP in mice was not altered by liver-stored vitamin A.; The results of present study suggest that the anticarcinogenic activity of retinoids may act on the initiation stage of carcinogenesis by inhibiting certain P-450 isozymes. |
