Hepatic Microsomal Metabolism of Carcinogens and Its Induction by Unrelated Chemicals

As noted by Trager (1980), the carcinogen DAB was the first xenobiotic to be studied in vitro for its metabolism by liver homogenates or microsomes. These studies by Mueller and Miller (1948) showed the 7V-demethyIation, reduction of the azo linkage, and aromatic ring-hydroxylation occurred on aerobic incubation of DAB with liver homogenates fortified with pyridine nucleotides and hexose diphosphate. Enzymatic reduction of the azo linkage was found predominantly in the microsome fraction (then called the small granule fraction) and was dependent on both NADPH and a flavin adenine dinucleotide-containing protein (Mueller and Miller, 1949, 1950). It was further shown that the enzymatic demethylation of 7V-monomethylaminoazo dyes depended on oxygen and NADPH with the formation of stoichiometric amounts of formaldehyde (Mueller and Miller, 1953). One of the substrates used in these studies was 3-methyl-4-monomethylaminoazobenzene (3-methyl-MAB). It proved to be very resistant to reduction of the azo linkage and formed equimolar amounts of 3-methyl-4-aminoazobenzene and formaldehyde. Further study of this oxidative demethylation enzyme system led unexpectedly to the finding that the liver homogenates of mice fed certain crude diets had activities two to three times greater than the liver homogenates of mice fed a purified diet (Brown el al., 1954). Several pure compounds, including pinane hydroperoxide and 3-methylcholanthrene, were active at low levels in the purified diet, but none were active in homogenates. With rat liver homogenates and microsomes, even larger increases up to 5-fold were observed with the inclusion of these pure compounds in the purified diet (Conney et al., 1956, 1957a). Several lines of evidence, including the strong inhibition by ethionine in the diet, suggested that these increases in demethylase activity were increases in the amount of the enzyme. Still larger increases of up to 10-fold were found in benzpyrene hydroxylase activity after ip injections of benzpyrene (Conney et al., 1957b). Subsequent studies with protein synthesis inhibitors demonstrated that these increases in enzyme activity were increases in the amount of enzyme (Conney et al., 1956; von der Decken and Hultin, 1960; Gelboin and Sokoloff, 1961; Gelboin and Blackburn, 1963; Conney and Gilman, 1963; Gelboin, 1964).

Today, a variety of microsomal oxidases dependent on NADPH and molecular oxygen are known (the large family of cytochromes P450 and flavoprotein enzymes) that metabolize a range of endogenous and exogenous substrates, including many carcinogens and other xenobiotics. Many of these enzymes are inducible by a range of chemicals.

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