Analysis of CA repeats in first intron of class I ADH gene in Long-Evans Cinnamon rats developing fatal intoxication after ethanol intake.
The Long-Evans Cinnamon (LEC) rat is a mutant strain established from Long-Evans rats that displays spontaneous hepatitis and liver cancer. We previously demonstrated that LEC rats died of acute ethanol intoxication after being fed a liquid diet containing 5% ethanol. Furthermore, we found that both alcohol dehydrogenase (ADH) and aldehyde dehydrogenase activities were remarkably suppressed in the liver of LEC rat, compared with Wistar rats. In the present study, we further investigated ethanol metabolism in the non-ADH pathway and what caused the decrease of liver ADH activity in LEC rats. Blood ethanol concentration 5 hr after intraperitoneal administration of ethanol in LEC rats was higher than in the Wistar rats, indicating that ethanol oxidation was impaired in LEC rats. The expression of liver cytochrome P-450IIE1 in the LEC rat was as much as that in Wistar rats. Regarding decreased ADH activity in the liver of LEC rats, we examined an alternating purine-pyrimidine (CA) repeat-length polymorphism in the first intron of a class I ADH gene that would play a role in altering ADH activity. A polymerase chain reaction method was used to amplify the CA repeat in the first intron of this class I ADH gene, a nine CA repeat insertion and a point mutation were detected in LEC rats. These results suggest that this alternating sequence would modify transcription of the class I ADH gene in LEC rats. Thus, LEC rats have abnormal ethanol metabolism in the ADH pathway.
Katsuki
S
S
Fourth Department of Internal Medicine, Sapporo Medical University School of Medicine, Japan.
Kato
J
J
Nakajima
M
M
Inui
N
N
Sasaki
K
K
Kohgo
Y
Y
Niitsu
Y
Y
D000426:Alcohol Dehydrogenase / Q000235:genetics*; D000435:Alcoholic Intoxication / Q000235:genetics*; D000818:Animals; D001483:Base Sequence / Q000235:genetics; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D000431:Ethanol / Q000493:pharmacokinetics / Q000633:toxicity*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D007438:Introns / Q000235:genetics*; D008114:Liver Neoplasms, Experimental / Q000235:genetics; D008297:Male; D008657:Metabolic Clearance Rate / Q000235:genetics; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics; D017354:Point Mutation / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length; D011685:Purine Nucleotides / Q000235:genetics*; D011742:Pyrimidine Nucleotides / Q000235:genetics*; D051381:Rats; D011919:Rats, Inbred Strains; D017208:Rats, Wistar
D011685:Purine Nucleotides; D011742:Pyrimidine Nucleotides; D000431:Ethanol; D003577:Cytochrome P-450 Enzyme System; D000426:Alcohol Dehydrogenase; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating