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-fol d increases, respectively, in the hepatic levels of aflatoxin B-1-dial dehyde reductase (AFAR) protein. By contrast, treatment of rats with e ither of the inducing agents phenobarbital or 3-methylcholanthrene res ults 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 lev els of hepatic AFAR protein are accompanied by corresponding increases in AFAR mRNA. Immunodepletion of AFAR from rat liver extracts has rev ealed that AFAR makes a considerable contribution to carbonyl metaboli sm in livers from animals treated with synthetic antioxidants and that it is the major reductase that can utilize aflotoxin B-1-dialdehyde a s a substrate. The immunodepletion experiments also revealed the prese nce of at least one other inducible carbonyl-reducing enzyme that, lik e AFAR, can metabolize 9,10-phenanthraquinone. Carbonyl-reducing activ ity 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-r educing enzymes are induced by ehtoxyquin, and that these are distinct from NAS(P)H: quinone oxidoreductase. Collectively, these data show t hat synthetic antioxidants can influence substantially the capacity of rat liver to metabolize reactive carbonyl-containing compounds.