The influence of co-exposure to dimethyldithiocarbamate on butadiene metabolism.
Treatment of rats and mice with a single oral dose of dimethyldithiocarbamate (DMDTC; 250 mg/kg) had a marked effect on hepatic CYP2E1 and aldehyde dehydrogenase activities, measured in vitro, for up to 24 h after dosing. The same treatment did not affect CYP2A6, glutathione S-transferase, epoxide hydrolase, alcohol dehydrogenase activities or hepatic glutathione levels. As a consequence of the loss of CYP2E1 activity, butadiene metabolism in liver fractions from DMDTC treated rats and mice was markedly reduced, as was the metabolism of the mono-epoxide to the di-epoxide in mouse liver. The conversion of the mono-epoxide to the diol by epoxide hydrolases was not affected by DMDTC treatment. Urinary excretion of radioactivity, following dosing with DMDTC and exposure to 200 ppm C-14 butadiene for 6 h, was markedly reduced in rats, but increased in mice. The profiles of urinary metabolites were qualitatively similar from mice exposed to butadiene to those exposed after dosing with DMDTC. In the rat, pre-dosing with DMDTC resulted in the formation of three additional urinary metabolites following exposure to butadiene. Overall, DMDTC appears to impact qualitatively and quantitatively on the metabolism of butadiene. The nature and full significance of these changes has yet to be characterised.
Green
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Zeneca Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire SK104TJ, UK. trevor.green@ctl.zeneca.com
Toghill
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A
Moore
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R
D000284:Administration, Oral; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D002070:Butadienes / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004125:Dimethyldithiocarbamate / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D004347:Drug Interactions; D004851:Epoxide Hydrolases / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D051381:Rats; D011916:Rats, Inbred F344; D013045:Species Specificity
D002070:Butadienes; D004125:Dimethyldithiocarbamate; D019392:Cytochrome P-450 CYP2E1; D000444:Aldehyde Dehydrogenase; D004851:Epoxide Hydrolases; C031763:1,3-butadiene