Modulation of experimental alcohol-induced liver disease by cytochrome P450 2E1 inhibitors.
This study was done to determine if a relationship exists between CYP2E1 induction by ethanol, lipid peroxidation, and liver pathology in experimental alcohol-induced liver disease in the rat. Rats were fed ethanol with or without diallyl sulfide (DAS) or phenethyl isothiocyanate (PIC) intragastrically for 1 month. CYP2E1 induction by ethanol was correlated with lipid peroxidation, liver microsomal CYP2E1 hydroxylation of paranitrophenol, and the liver pathology score using the data from the PIC-fed rats. Some of the data from the ethanol and DAS-fed rats were not included here because they have been reported elsewhere. Microsomal CYP2E1 protein levels induction by ethanol was decreased by PIC ingestion. Similarly, PIC reduced the increase microsomal reduced form of nicotinamide-adenine dinucleotide (NADPH)-dependent lipid peroxidation and p-nitrophenol hydroxylase (PNPH) activity, induced by ethanol feeding. The lipid peroxidation was reduced to below control levels; however, the pathology score was partially but not significantly reduced by isothiocyanate feeding. CYP2E1 messenger RNA (mRNA) was decreased by both inhibitors of CYP2E1. Immunohistochemical staining of liver for CYP2E1 protein showed that the lobular distribution of the isozyme changed from the centrilobular to a diffuse pattern, with an increase in the periportal region when the CYP2E1 inhibitors were fed with ethanol, and that this change correlated with the change in the distribution of fat in the lobule. The data support the idea that there is a link between CYP2E1 induction by ethanol and the early phase of ethanol-induced liver injury in this rat model. This link may involve lipid peroxidation, but other factors related to CYP2E1 induction must also be involved.
Morimoto
M
M
Department of Pathology, Harbor-UCLA Medical Center, Torrance 90509, USA.
Hagbjörk
A L
AL
Wan
Y J
YJ
Fu
P C
PC
Clot
P
P
Albano
E
E
Ingelman-Sundberg
M
M
French
S W
SW
D000284:Administration, Oral; D000498:Allyl Compounds; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D019392:Cytochrome P-450 CYP2E1; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D000431:Ethanol / Q000633:toxicity; D017403:In Situ Hybridization; D017879:Isothiocyanates / Q000008:administration & dosage / Q000494:pharmacology*; D008099:Liver / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D009929:Organ Size / Q000187:drug effects; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D013440:Sulfides / Q000008:administration & dosage / Q000494:pharmacology*
D000498:Allyl Compounds; D016588:Anticarcinogenic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D017879:Isothiocyanates; D013440:Sulfides; D000431:Ethanol; C038491:allyl sulfide; C058305:phenethyl isothiocyanate; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating