DO ENDOGENOUS VOLATILE ORGANIC-CHEMICALS MEASURED IN BREATH REFLECT AND MAINTAIN CYP2E1 LEVELS IN-VIVO

The effect of trans-1,2-dichloroethylene (DCE), an inhibitor of cytoch rome P450 (P450) 2E1 (CYP2E1), on the composition and quantity of vola tile organic chemicals (VOCs) expired in the breath of male F-344 rats was determined in parallel with hepatic P450 activity and content. He patic microsomes were prepared from groups of rats prior to dosing and at 2, 5, 12, and 24 hr postdosing with DCE (100 mg/kg ip), and total P450 content and the activity of CYP2E1 was determined. Breath was col lected from parallel groups of rats predose and at several intervals t hat encompassed the time points for rats euthanized for microsome prep aration. Over 100 breath components were identified by GC/MS and quant itated by GC/FID. The overall change in the profile of breath VOCs res ulting from administration of DCE was striking. An increase of approxi mately 1000% was measured in the mass of non-DCE-derived VOCs exhaled 4-6 hr after dosing, but there was no increase in hepatic lipid peroxi dation. In addition to hexane, short-chain methyl ketones were particu larly affected, and percentage increases in response to inhibition wer e inversely related to chain length, with acetone and 2-butanone > 2-p entanone much greater than 2-hexanone > 2-heptanone. There were no sta tistically significant decreases in total content of P450, but the act ivity of CYP2E1 was diminished about 65% at 2 and 5 hr after DCE treat ment. However, 24 hr after inhibitor administration the total mass of VOCs expired was only marginally elevated above baseline and CYP2E1 ac tivity was not significantly different from that of untreated rats. Th e compounds most markedly increased upon inhibition of CYP2E1 are also excellent inducers of that isozyme, and this finding is consistent wi th the hypothesis that these chemicals are important to the normal hom eostasis of CYP2E1. The increase in breath components observed followi ng inhibition of CYP2E1 suggests that VOCs in breath can reflect the a ctivity of that isozyme in vivo. (C) 1997 Academic Press.