The role of hydrolysis in the detoxification of 1,2:3,4-diepoxybutane by human, rat, and mouse liver and lung in vitro.
1,2:3,4-Diepoxybutane (BDE) is probably the ultimate genotoxic metabolite of the rodent carcinogen 1,3-butadiene (BD). The formation of BDE from BD has been characterized in vitro using tissues from rats, mice, and humans. For assessment of human risk following exposure to BD, a quantitative understanding between the balance of formation and inactivation of BDE is essential. BDE can be removed by glutathione (GSH) conjugation and by hydrolysis. Recently, significant species differences were reported in GSH conjugation of BDE in vitro, with rats being more efficient than humans and mice being much more efficient than either rats or humans (Boogaard et al., Toxicol. Appl. Pharmacol. 136, 307, 1996). In the present study the microsomal hydrolysis of BDE was quantified using tissues of rats, mice, and humans. Hydrolysis of BDE was well described by Michaelis-Menten kinetics. Two metabolites, erythritol and anhydroerythritol, were identified following incubation of BDE with human microsomes, but these metabolites did not fully account for the disappearance of BDE, suggesting that there may be other as yet unidentified routes of metabolism. In contrast to GSH conjugation, which was most efficient in mice compared with rats or humans, the efficiency of hydrolysis as expressed by Vmax/Km was much lower in mouse (3.93 microl/min/mg protein) than in rat (19.2) or human (32.5) liver. Pulmonary hydrolysis was also most efficient in humans, with average Vmax/Km values of 7.7, 6.7, and 2.7 microl/min/mg protein for humans, mice, and rats, respectively. However, the interindividual variation among the human samples was considerable with individual Vmax/Km values varying from 17.9 to 49.5 microl/min/mg protein for liver and from 4.57 to 16.2 microl/min/mg protein for lung tissue. This means that the heterogeneity among humans in the formation as well as in the removal of BDE will be an important factor in human risk assessment. The present data, coupled with earlier studies on formation and removal of BDE and the observation that GSH conjugation of BDE is a potentially mutagenic pathway, explain the high susceptibility of mice to BD-induced carcinogenesis.
Boogaard
P J
PJ
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709-2137, USA.
Bond
J A
JA
D000818:Animals; D004852:Epoxy Compounds / Q000493:pharmacokinetics*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D008658:Inactivation, Metabolic; D008099:Liver / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D008297:Male; D051379:Mice; D009153:Mutagens / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
D004852:Epoxy Compounds; D009153:Mutagens; C007366:diepoxybutane; D005978:Glutathione