Modifications of carcinogen metabolism in hepatic microsomes of suckling young by 3-methylcholanthrene or beta-naphthoflavone administered to lactating rats.
The effects of treating lactating rats with 3-methylcholanthrene (3-MC) or beta-naphthoflavone (beta-NF) (three i.p. injections of 20 or 40 mg compound/kg of body weight) on hepatic microsomal enzymes of their suckling young were examined. This treatment had no apparent effect on the contents of cytochromes P-450 and b5 or on the activities of NADH- and NADPH-cytochrome c reductases in hepatic microsomes of the pups. However, these microsomes had 8- and 6-fold increased capacities for hydroxylations of benzo[a]pyrene (B[a]P) and N-2-fluorenylacetamide (2-FAA) respectively. These increases were about 5-fold greater in the hepatic microsomes of the dams, in which they were inhibited by 0.1 mM alpha-naphthoflavone (alpha-NF) in vitro 72-81 and 89-95% and by 0.1 mM beta-NF in vitro 12-41 and 60-76% respectively. In the pups, the induced activities were also inhibited, whereas the basal hydroxylations of B[a]P and 2-FAA were stimulated by alpha-NF 2.7- and 5.0-fold and by beta-NF 1.4- and 2.4-fold respectively. The inhibition of the induced hydroxylations by alpha-NF and beta-NF may be explained by their higher affinities (Ks, 0.14 and 0.28 microM, respectively) than those of B[a]P and 2-FAA (Ks, 4.4 to 8.8 and 2.4 to 3.1 microM, respectively) for cytochrome P-450. Whereas beta-NF gave a type I binding spectrum, alpha-NF gave a spectrum composed of type I and reverse-type I elements. Analysis of metabolites of 2-FAA showed differences in their type and amounts formed by hepatic microsomes of beta-NF-treated lactating rats and their pups. Thus, in the dams the formation of 1-, 3-, 5-, 7-, 9- and N-hydroxy-2-FAA was increased by 9-, 30-, 40-, 5-, 20- and 5-fold respectively. In the pups, the formation of 1-, 3-, 5-, 7- and N-hydroxy-2-FAA was increased by 2-, 30-, 18-, 4- and 27-fold respectively. All these increased hydroxylations were inhibited by 0.1 mM alpha-NF in vitro. In the hepatic microsomes of pups from the corn oil-treated dams, alpha-NF stimulated all ring-hydroxylations, but not N-hydroxylation of 2-FAA. The results support earlier findings that microsomal enzymes differ in immature and mature rat liver and suggest that N-hydroxylation of 2-FAA, the activation required for carcinogenesis, and specific ring-hydroxylations are catalyzed by different cytochrome P-450 isozymes.(ABSTRACT TRUNCATED AT 400 WORDS)
D015073:2-Acetylaminofluorene / Q000378:metabolism; D000828:Animal Population Groups / Q000378:metabolism*; D000818:Animals; D000833:Animals, Suckling / Q000378:metabolism*; D001564:Benzo(a)pyrene; D001571:Benzoflavones / Q000494:pharmacology*; D001580:Benzopyrenes / Q000378:metabolism; D002273:Carcinogens / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D006900:Hydroxylation; D007774:Lactation; D008748:Methylcholanthrene / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D011247:Pregnancy; D051381:Rats; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D001580:Benzopyrenes; D002273:Carcinogens; D005419:Flavonoids; D001564:Benzo(a)pyrene; D008748:Methylcholanthrene; D019324:beta-Naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D015073:2-Acetylaminofluorene