MODULATION OF EXPERIMENTAL ALCOHOL-INDUCED LIVER-DISEASE BY CYTOCHROME-P450 2E1 INHIBITORS

This study was done to determine if a relationship exists between CYP2 E1 induction by ethanol, lipid peroxidation, and liver pathology in ex perimental alcohol-induced liver disease in the rat. Rats were fed eth anol with or without diallyl sulfide (DAS) or phenethyl isothiocyanate (PIC) intragastrically for 1 month. CYP2E1 induction by ethanol was c orrelated with lipid peroxidation, liver microsomal CYP2E1 hydroxylati on of paranitrophenol, and the liver pathology score using the data fr om the PIC-fed rats. Some of the data from the ethanol and DAS-fed rat s were not included here because they have been reported elsewhere. Mi crosomal CYP2E1 protein levels induction by ethanol was decreased by P IC ingestion. Similarly, PIG reduced the increase microsomal reduced f orm of nicotinamide-adenine dinucleotide (NADPH)-dependent Lipid perox idation and p-nitrophenol hydroxylase (PNPH) activity, induced by etha nol feeding. The lipid peroxidation was reduced to below control level s; however, the pathology score was partially but not significantly re duced by isothiocyanate feeding. CYP2E1 messenger RNA (mRNA) was decre ased by both inhibitors of CYP2E1, Immunohistochemical staining of liv er for CYP2E1 protein showed that the lobular distribution of the isoz yme changed from the centrilobular to a diffuse pattern, with an incre ase in the periportal region when the CYP2E1 inhibitors were fed with ethanol, and that this change correlated with the change in the distri bution of fat in the lobule. The data support the idea that there is a link between GYP2E1 induction by ethanol and the early phase of ethan ol-induced liver injury in this rat model. This link may involve lipid peroxidation, but other factors related to CYP2E1 induction must also be involved.