Regulation of carbonyl-reducing enzymes in rat liver by chemoprotectors.

Feeding rats on diets containing the synthetic antioxidants ethoxyquin, butylated hydroxyanisole, and oltipraz results in 15-, 9-, and 6-fold increases, respectively, in the hepatic levels of aflatoxin B1-dialdehyde reductase (AFAR) protein. By contrast, treatment of rats with either of the inducing agents phenobarbital or 3-methylcholanthrene results in an approximate increase of only 1.4-fold in the amount of AFAR in rat liver. Northern blotting has shown that these increases in levels of hepatic AFAR protein are accompanied by corresponding increases in AFAR mRNA. Immunodepletion of AFAR from rat liver extracts has revealed that AFAR makes a considerable contribution to carbonyl metabolism in livers from animals treated with synthetic antioxidants and that it is the major reductase that can utilize aflatoxin B1-dialdehyde as a substrate. The immunodepletion experiments also revealed the presence of at least one other inducible carbonyl-reducing enzyme that, like AFAR, can metabolize 9,10-phenanthraquinone. Carbonyl-reducing activity from rat liver has been resolved into six enzyme-containing peaks by anion-exchange chromatography on Q-Sepharose. This method has been used to show that, in addition to AFAR, two other rat liver carbonyl-reducing enzymes are induced by ethoxyquin, and that these are distinct from NAD(P)H: quinone oxidoreductase. Collectively, these data show that synthetic antioxidants can influence substantially the capacity of rat liver to metabolize reactive carbonyl-containing compounds.