Evidence for Involvement of Alcohol Dehydrogenase and Cytochrome P450
Abstract
3-Butene-1,2-diol (BDD), a metabolite of 1,3-butadiene, is rapidly metabolized by B6C3F1 mice at doses ranging from 10 to 250 mg/kg. Calculation of plasma clearance suggested that the kinetics of BDD metabolism were dose-dependent. Clearance varied 5-fold in this dose range. Urinary excretion of BDD was also dose-dependent but did not exceed 5% of the administered dose. A small fraction of the dose (<1%) was excreted as glucuronide or sulfate conjugates. Benzylimidazole, a cytochrome P450 inhibitor, decreased the clearance of BDD (25 mg/kg) by 44%, whereas 4-methylpyrazole, an alcohol dehydrogenase and cytochrome P450 inhibitor, decreased BDD clearance by 82%. BDD administration (250 mg/kg) resulted in depletion of hepatic and renal nonprotein thiols, by 48 and 22%, respectively. Pretreatment of mice with 4-methylpyrazole provided partial protection against depletion of nonprotein thiols, whereas pretreatment with benzylimidazole was ineffective. Incubation of BDD with NADPH and mouse liver microsomes resulted in time-dependent inactivation ofp-nitrophenol hydroxylase (PNPH) activity, a marker for cytochrome P450. Inclusion of glutathione, with or without glutathione peroxidase, did not attenuate the inactivation of PNPH, whereas deferoxamine, superoxide dismutase, catalase, and mannitol provided modest protection. These results are consistent with suicide inhibition of PNPH by BDD, with a minor role for reactive oxygen species in the loss of PNPH. Treatment of mice with BDD (250 mg/kg) inactivated hepatic microsomal PNPH activity by 50% after 60 min. These results suggest that BDD is extensively and rapidly metabolized in mice, and they provide evidence for the formation of reactive intermediates that could play a role in the toxicity of 1,3-butadiene.
Footnotes
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Send reprint requests to: Dr. Adnan Elfarra, Department of Comparative Biosciences, University of Wisconsin School of Veterinary Medicine, 2015 Linden Dr. West, Madison, WI 53706.
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This research was supported by National Institute of Environmental Health Sciences Grant 9-R01-ES06841.
- Abbreviations used are::
- BD
- 1,3-butadiene
- BDD
- 3-butene-1,2-diol
- BMO
- butadiene monoepoxide
- HMVK
- hydroxymethylvinyl ketone
- TMS
- trimethylsilyl
- MP
- 4-methylpyrazole
- ADH
- alcohol dehydrogenase
- BI
- 1-benzylimidazole
- NPT
- nonprotein thiol
- PNPH
- p-nitrophenol hydroxylase
- GSH
- reduced glutathione
- ROS
- reactive oxygen species
- P450
- cytochrome P450
- Received November 19, 1997.
- Accepted May 18, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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