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 cytochrome P450 (P450) 2E1 (CYP2E1), on the composition and quantity of volatile organic chemicals (VOCs) expired in the breath of male F-344 rats was determined in parallel with hepatic P450 activity and content. Hepatic 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 collected from parallel groups of rats predose and at several intervals that encompassed the time points for rats euthanized for microsome preparation. Over 100 breath components were identified by GC/MS and quantitated by GC/FID. The overall change in the profile of breath VOCs resulting from administration of DCE was striking. An increase of approximately 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 peroxidation. In addition to hexane, short-chain methyl ketones were particularly affected, and percentage increases in response to inhibition were inversely related to chain length, with acetone and 2-butanone > 2-pentanone >> 2-hexanone > 2-heptanone. There were no statistically significant decreases in total content of P450, but the activity of CYP2E1 was diminished about 65% at 2 and 5 hr after DCE treatment. However, 24 hr after inhibitor administration the total mass of VOCs expired was only marginally elevated above baseline and CYP2E1 activity was not significantly different from that of untreated rats. The compounds most markedly increased upon inhibition of CYP2E1 are also excellent inducers of that isozyme, and this finding is consistent with the hypothesis that these chemicals are important to the normal homeostasis of CYP2E1. The increase in breath components observed following inhibition of CYP2E1 suggests that VOCs in breath can reflect the activity of that isozyme in vivo.
Mathews
J M
JM
Research Triangle Institute, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA. mathews@rti.org
Raymer
J H
JH
Etheridge
A S
AS
Velez
G R
GR
Bucher
J R
JR
D000096:Acetone / Q000032:analysis; D000818:Animals; D001944:Breath Tests; D002074:Butanones / Q000032:analysis; D019392:Cytochrome P-450 CYP2E1 / Q000032:analysis* / Q000378:metabolism; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004000:Dichloroethylenes / Q000008:administration & dosage / Q000633:toxicity*; D008401:Gas Chromatography-Mass Spectrometry; D006586:Hexanes / Q000032:analysis; D006838:Hydrocarbons / Q000032:analysis*; D007274:Injections, Intraperitoneal; D007659:Ketones / Q000032:analysis*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008745:Methylation; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D010422:Pentanones / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344; D013379:Substrate Specificity; D014835:Volatilization
D002074:Butanones; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004000:Dichloroethylenes; D006586:Hexanes; D006838:Hydrocarbons; D007659:Ketones; D010422:Pentanones; D000096:Acetone; C026385:n-hexane; C005222:methylethyl ketone; C011917:2-heptanone; D019392:Cytochrome P-450 CYP2E1; C076402:2-pentanone; C035384:1,2-dichloroethylene