Comparison of the biotransformation of 1,3-butadiene and its metabolite, butadiene monoepoxide, by hepatic and pulmonary tissues from humans, rats and mice.
1,3-Butadiene (BD), a widely used monomer in the production of synthetic rubber and other resins, is one of the 189 hazardous air pollutants identified in the 1990 Clean Air Act Amendments. BD induces tumors at multiple organ sites in B6C3F1 mice and Sprague-Dawley rats; mice are much more susceptible to the carcinogenic action of BD than are rats. Previous in vivo studies have indicated higher circulating blood levels of butadiene monoepoxide (BMO), a potential carcinogenic metabolite of BD, in mice compared to rats, suggesting that species differences in the metabolism of BD may be responsible for the observed differences in carcinogenic susceptibility. The metabolic fate of BD in humans is unknown. The objective of these studies was to quantitate in vitro species differences in the oxidation of BD and BMO by cytochrome P450-dependent monooxygenases and the inactivation of BMO by epoxide hydrolases and glutathione S-transferases using microsomal and cytosolic preparations of livers and lungs obtained from Sprague-Dawley rats, B6C3F1 mice and humans. Maximum rates for BD oxidation (Vmax) were highest for mouse liver microsomes (2.6 nmol/mg protein/min) compared to humans (1.2) and rats (0.6). The Vmax for BD oxidation by mouse lung microsomes was similar to that of mouse liver but greater than 10-fold higher than the Vmax for the reaction in human or rat lung microsomes. Correlation analysis revealed that P450 2E1 is the major P450 enzyme responsible for oxidation of BD to BMO. Only mouse liver microsomes displayed quantifiable rates for metabolism of BMO to butadiene diepoxide (Vmax = 0.2 nmol/mg protein/min), a known rodent carcinogen. Human liver microsomes displayed the highest rate of BMO hydrolysis by epoxide hydrolases. The Vmax in human liver microsomes ranged from 9 to 58 nmol/mg protein/min and was at least 2-fold higher than the Vmax observed in mouse and rat liver microsomes. The Vmax for glutathione S-transferase-catalyzed conjugation of BMO with glutathione was highest for mouse liver cytosol (500 nmol/mg protein/min) compared to human (45) or rat (241) liver cytosol. In general, the KMs for the detoxication reactions were 1000-fold higher than the KMs for the oxidation reaction. Because of the low solubility of the BD and the relatively high KM for oxidation, it is likely that the Vmax/KM ratio will be important for BD and BMO metabolism in vivo. In vivo clearance constants were calculated from in vitro data for BD oxidation and BMO oxidation, hydrolysis and GSH conjugation.(ABSTRACT TRUNCATED AT 400 WORDS)
Csanády
G A
GA
Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709.
Guengerich
F P
FP
Bond
J A
JA
D000818:Animals; D001711:Biotransformation; D002070:Butadienes / Q000378:metabolism* / Q000493:pharmacokinetics; D002273:Carcinogens / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D004852:Epoxy Compounds / Q000378:metabolism* / Q000493:pharmacokinetics; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D008297:Male; D008433:Mathematics; D051379:Mice; D008815:Mice, Inbred Strains; D008861:Microsomes / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D008954:Models, Biological; D009928:Organ Specificity; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity
D002070:Butadienes; D002273:Carcinogens; D004852:Epoxy Compounds; C024370:3,4-epoxy-1-butene; C031763:1,3-butadiene