Inhibition of CYP2E1 activity does not abolish pulsatile urine alcohol concentrations during chronic alcohol infusions.
Continuous, long-term intragastric infusions of ethanol leads to a two-step induction of hepatic cytochrome P450 2E1 (CYP2E1) that is correlated with blood ethanol concentrations (BECs) and urine alcohol concentrations (UECs). In addition, long-term and continuous ethanol infusion does not produce a steady-state BEC, but results in pulsatile BECs and UECs having peak-peak duration of approximately 6 days and ethanol concentrations ranging from near zero to over 500 mg/dl. In the present study, rats were treated with ethanol (levels reaching 13 g.kg-1.day-1) for 38 days in the presence of compounds reported to block CYP2E1 activity or expression, to study the possible involvement of CYP2E1 in the pulsatile BECs. The inhibitors used were chlormethiazole (CMZ); diallysulfide (DAS); phenethyl isothiocyanate (PET) and dihydrocapsacin (DHC). Hepatic microsomal metabolism of carbon tetrachloride and p-nitrophenol, as well as mean CYP2E1 apoprotein levels, were significantly greater (P < or = 0.05) in ethanol-treated rats than in control rats, whereas rats treated with DAS, CMZ or PET had significantly (P < or = 0.05) reduced p-nitrophenol and carbon tetrachloride metabolism and lower CYP2E1 apoprotein levels compared to those of ethanol controls. UECs were variable in all ethanol-treated groups and there was a typical pulsatile pattern that had a mean interpulse interval (the number of days between the peaks of two consecutive pulses) ranging over 5.4 +/- 0.3-6.0 +/- 0.7 days and a mean amplitude (nadir to peak UEC) of 415 +/- 39-337 +/- 33 mg/dl. None of the putative CYP2E1 blockers altered the pulsatile nature of ethanol in urine. Our results suggest that pulsatile UECs are not the result of variations in the amount of CYP2E1.
Badger
T M
TM
Department of Pediatrics, Arkansas Children's Hospital Research Institute, Little Rock, USA.
Ronis
M J
MJ
Ingelman-Sundberg
M
M
Hakkak
R
R
D000818:Animals; D002251:Carbon Tetrachloride / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D000431:Ethanol / Q000097:blood / Q000633:toxicity / Q000652:urine*; D006128:Growth / Q000187:drug effects; D008297:Male; D009596:Nitrophenols / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors* / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar
D065607:Cytochrome P-450 Enzyme Inhibitors; D009596:Nitrophenols; D012333:RNA, Messenger; D000431:Ethanol; D003577:Cytochrome P-450 Enzyme System; D002251:Carbon Tetrachloride; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating; C024836:4-nitrophenol