Cytochrome P450 CYP 2E1 induction during chronic alcohol exposure occurs by a two-step mechanism associated with blood alcohol concentrations in rats.
Intragastric infusion of ethanol to male rats as part of a system of total enteral nutrition allows chronic ethanol treatment without the nutritional and feeding problems associated with traditional liquid diets. Even though ethanol was infused at a constant rate 24 h a day, blood alcohol concentrations were observed to cycle over a 5- to 7-day period from values less than 10 mg/dl to greater than 400 mg/dl. Examination of the hepatic microsomal mono-oxygenase system in animals chronically treated with ethanol using this model revealed variable induction of cytochrome P450 CYP 2E1, the principal component of the microsomal ethanol oxidizing system. Correlations were observed between urine alcohol concentrations (UACs) and 1) the level of expression of CYP 2E1 mRNA in Northern blot analysis, 2) the level of CYP 2E1 apoprotein in Western blot analysis and, 3) microsomal p-nitrophenol (PNP) hydroxylation. The data from ethanol-treated animals were expressed as low UAC group (UACs < 200 mg/dl) and a high UAC group (UACs > 300 mg/dl) and compared to total enteral nutrition controls. In the low UAC group, a 6- to 7-fold induction in microsomal PNP hydroxylase (a CYP 2E1-dependent activity) was accompanied by a 4- to 5-fold increase in CYP 2E1 apoprotein, but no increase in CYP 2E1 mRNA levels. In contrast, in the high UAC group, induction of PNP hydroxylase was 15- to 16-fold, induction of CYP 2E1 apoprotein was 12- to 13-fold and CYP 2E1 mRNA was elevated 5- to 6-fold.(ABSTRACT TRUNCATED AT 250 WORDS)
Ronis
M J
MJ
Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock.
Huang
J
J
Crouch
J
J
Mercado
C
C
Irby
D
D
Valentine
C R
CR
Lumpkin
C K
CK
Ingelman-Sundberg
M
M
Badger
T M
TM
D000426:Alcohol Dehydrogenase / Q000502:physiology; D000818:Animals; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D004750:Enteral Nutrition; D004790:Enzyme Induction / Q000187:drug effects; D000431:Ethanol / Q000008:administration & dosage / Q000097:blood* / Q000494:pharmacology*; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley
D012333:RNA, Messenger; D000431:Ethanol; D003577:Cytochrome P-450 Enzyme System; D000426:Alcohol Dehydrogenase; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating