Benzene metabolism by ethanol-, acetone-, and benzene-inducible cytochrome P-450 (IIE1) in rat and rabbit liver microsomes.
Ethanol is known to exert a synergistic effect on the toxicity of benzene. In the present investigation it was found that benzene was metabolized at a rate 20-65-fold higher in liver microsomes from ethanol- or acetone-treated rats than in microsomes from control animals. One high affinity site [Km = 19 +/- 5 (SD) microM] and one low affinity site [Km = 0.3 +/- 0.1 mM] for benzene metabolism were present in microsomes of acetone-treated rats, and similar sites were seen in microsomes from control or ethanol-treated rats. Treatment of the animals with either ethanol or acetone mainly influenced the Vmax values for benzene metabolism. Also benzene treatment of rats caused an increased rate of microsomal benzene metabolism. The hepatic microsomal NADPH-dependent metabolism of benzene was inhibited by compounds known to interact with the ethanol-inducible form of P-450 such as imidazole, ethanol, aniline, and acetone but was unaffected by addition of metyrapone. Anti-IgG against ethanol-inducible cytochrome P-450 from rat (P-450j) or rabbit liver (P-450 LMeb) inhibited the microsomal benzene metabolism effectively in rat or rabbit liver microsomes, respectively, whereas preimmune IgG was without effect. The level of rat ethanol-inducible P-450 (P-450j) was induced to an extent similar to that for the microsomal benzene metabolism, by either benzene, acetone, or ethanol. The data indicate that benzene is metabolized mainly by the ethanol-inducible P-450 form in liver microsomes and that the induction of this isozyme by ethanol can provide an explanation for the synergistic action of ethanol on benzene toxicity.
Johansson
I
I
Department of Physiological Chemistry, Karolinska Institute, Stockholm, Sweden.
Ingelman-Sundberg
M
M
D000096:Acetone / Q000494:pharmacology*; D000818:Animals; D001554:Benzene / Q000378:metabolism* / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction; D000431:Ethanol / Q000494:pharmacology*; D007527:Isoenzymes / Q000096:biosynthesis*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D007527:Isoenzymes; D000096:Acetone; D000431:Ethanol; D003577:Cytochrome P-450 Enzyme System; D001554:Benzene