Metabolism and covalent binding of [14C]toluene by human and rat liver microsomal fractions and liver slices.
The in vitro metabolism of [14C]toluene by liver microsomes and liver slices from male Fischer F344 rats and human subjects has been compared. Rat liver microsomes produced only benzyl alcohol from toluene. Liver microsomes from human subjects metabolized toluene to benzyl alcohol, benzaldehyde, and benzoic acid. Liver microsomes from one human donor also produced p-cresol and o-cresol. The overall rate of toluene metabolism by human liver microsomes was 9-fold greater than by rat liver microsomes. Human liver microsomal metabolism of benzyl alcohol to benzaldehyde required NADPH and was inhibited by carbon monoxide and high pH (pH 10). but was not inhibited by ADP-ribose or sodium azide. These results suggest that cytochrome P-450, rather than alcohol dehydrogenase, was responsible for the metabolism of benzyl alcohol to benzaldehyde. Human and rat liver slices metabolized toluene to hippuric acid and benzoic acid. The overall rate of toluene metabolism by human liver slices was 1.3-fold greater than by rat liver slices. Cresols and cresol conjugates were not detected in human or rat liver slice incubations. Covalent binding of [14C]toluene to human liver microsomes and slices was 21-fold and 4-fold greater than to the comparable rat liver preparations. Covalent binding did not occur in the absence of NADPH, was significantly decreased by coincubation with cysteine, glutathione, or superoxide dismutase, and was unaffected by coincubation with lysine. Protease and ribonuclease digestion decreased the amount of toluene covalently bound to human liver microsomes by 78% and 27% respectively. Acid washing of human liver microsomes had no effect on covalent binding.(ABSTRACT TRUNCATED AT 250 WORDS)
Chapman
D E
DE
Department of Pharmacology, Mayo Clinic & Foundation Rochester, MN 55905.
Moore
T J
TJ
Michener
S R
SR
Powis
G
G
D000428:Alcohol Drinking; D000818:Animals; D019905:Benzyl Alcohol; D001592:Benzyl Alcohols / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D011916:Rats, Inbred F344; D012907:Smoking / Q000378:metabolism; D013056:Spectrophotometry, Ultraviolet; D014050:Toluene / Q000378:metabolism*
D001592:Benzyl Alcohols; D014050:Toluene; D019905:Benzyl Alcohol