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The role of hydrolysis in the detoxification of 1,2:3,4-diepoxybutane by human, rat, and mouse liver and lung in vitro. 1996

P J Boogaard, and J A Bond
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709-2137, USA.

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.

UI MeSH Term Description Entries
D008099 Liver A large lobed glandular organ in the abdomen of vertebrates that is responsible for detoxification, metabolism, synthesis and storage of various substances. Livers
D008168 Lung Either of the pair of organs occupying the cavity of the thorax that effect the aeration of the blood. Lungs
D008297 Male Males
D008658 Inactivation, Metabolic Reduction of pharmacologic activity or toxicity of a drug or other foreign substance by a living system, usually by enzymatic action. It includes those metabolic transformations that make the substance more soluble for faster renal excretion. Detoxication, Drug, Metabolic,Drug Detoxication, Metabolic,Metabolic Detoxication, Drug,Detoxification, Drug, Metabolic,Metabolic Detoxification, Drug,Metabolic Drug Inactivation,Detoxication, Drug Metabolic,Detoxication, Metabolic Drug,Detoxification, Drug Metabolic,Drug Inactivation, Metabolic,Drug Metabolic Detoxication,Drug Metabolic Detoxification,Inactivation, Metabolic Drug,Metabolic Drug Detoxication,Metabolic Inactivation
D009153 Mutagens Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. Clastogen,Clastogens,Genotoxin,Genotoxins,Mutagen
D004852 Epoxy Compounds Organic compounds that include a cyclic ether with three ring atoms in their structure. They are commonly used as precursors for POLYMERS such as EPOXY RESINS. Epoxide,Epoxides,Epoxy Compound,Oxiranes,Compound, Epoxy,Compounds, Epoxy
D005978 Glutathione A tripeptide with many roles in cells. It conjugates to drugs to make them more soluble for excretion, is a cofactor for some enzymes, is involved in protein disulfide bond rearrangement and reduces peroxides. Reduced Glutathione,gamma-L-Glu-L-Cys-Gly,gamma-L-Glutamyl-L-Cysteinylglycine,Glutathione, Reduced,gamma L Glu L Cys Gly,gamma L Glutamyl L Cysteinylglycine
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D006868 Hydrolysis The process of cleaving a chemical compound by the addition of a molecule of water.
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia

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