Modulation of experimental alcohol-induced liver disease by cytochrome P450 2E1 inhibitors

doi:10.1016/0270-9139(95)90466-2

Hepatology

Volume 21, Issue 6, June 1995, Pages 1610-1617

https://doi.org/10.1016/0270-9139(95)90466-2 Get rights and content

Abstract

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.

References (50)

H Rouach et al.
Hepatic lipid peroxidation and mitochondrial susceptibility to peroxidative attacks during ethanol inhalation and withdrawal
Biochim Biophys Acta
(1983)
E Albano et al.
Spin trapping of free radical intermediates produced during the metabolism of isoniazid and iproniazid in isolated hepatocytes
Biochem Parmacol
(1987)
S Puntarulo et al.
Increased NADPH-dependent chemiluminescence by microsomes after chronic ethanol consumption
Arch Biochem Biophys
(1988)
G Ekstrom et al.
Rat liver microsomal NADPH-supported oxidase activity and lipid peroxidation dependent on ethanol-inducible cytochrome P-450 (P-450 IIE1)
Biochem Pharmacol
(1989)
E Albano et al.
Role of ethanol-inducible cytochrome P450 (P450 IIE1) in catalysing the free radical activation of aliphatic alcohols
Biochem Pharmacol
(1991)
M Ingelman-Sundberg et al.
Mechanisms of hydrosyl radical formation and ethanol oxidation by ethanol-inducible and other forms of rabbit liver microsomal cytochrome P-450
J Biol Chem
(1984)
M Ingelman-Sundberg et al.
Centrilobular expression of ethanol-inducible cytochrome P-450 (IIE1) in rat liver
Biochem Biophys Res Commun
(1988)
M Ingelman-Sundberg et al.
Ethanol-inducible cytochrome P450 2E1: genetic polymorphism, regulation and possible role in the etiology of alcohol-induced liver disease
Alcohol
(1993)
SW French et al.
Effect of ethanol on cytochrome P450 2E1 (CYP2E1), lipid peroxidation, and serum protein adduct formation in relation to liver pathology pathogenesis
Exp Mol Pathol
(1993)
H Tsukamoto
Oxidative stress, antioxidants, and alcoholic liver fibrogenesis
Alcohol
(1993)

M Morimoto et al.

Role of cytochrome P450 2E1 in alcoholic liver disease pathogenesis

Alcohol

(1993)

H Tsukamoto et al.

Introduction: evolution of intragastric ethanol infusion model

Alcohol

(1993)

JF Brady et al.

Modulation of rat hepatic microsomal monooxygenase activities and cytotoxicity by diallyl sulfide

Toxicol Appl Pharmacol

(1991)

P Chomczynski et al.

Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction

Anal Biochem

(1987)

EN Southern

Detection of specific sequences among DNA fragments separated by gel electrophoresis

J Mol Biol

(1975)

B-J Song et al.

Complementary DNA and protein sequences of ethanol-inducible rat and human cytochrome P-450s

J Biol Chem

(1986)

TM Badger et al.

Pulsatile blood alcohol and CYP2E1 induction during chronic alcohol infusions in rats

Alcohol

(1993)

J Pan et al.

Transcriptional activation of cytochrome P450 2B1/2 genes in rat liver by diaaly sulfide, a compound derived from garlic

Arch Biochem Biophys

(1993)

M Ingelman-Sundberg et al.

Centrilobular expression of ethanol-inducible cytochrome P450 (IIE1) in rat liver

Biochem Biophys Res Commun

(1988)

M Parola et al.

Stimulation of lipid peroxidation or 4-hydroxymonenal treatment increased procollagen α1(1) gene expression in human liver fat storing cells

Biochem Biophys Res Commun

(1993)

S Shaw et al.

Ethanol-induced lipid peroxidation: potentiation by long-term alcohol feeding and attenuation by methionine

J Lab Clin Med

(1981)

J Harata et al.

Effect of prolonged alcohol administration on activities of various enzymes scavenging activated oxygen radicals and lipid peroxide level in the liver of rats

Biochem Pharmacol

(1983)

LA Reinke et al.

Reactive free radical generation in vivo in heart and liver of ethanol-fed rats: correlation with radical formation in vitro

M Ingelman-Sundberg et al.

Lipid peroxidation dependent on ethanol-inducible cytochrome P-450 from rat liver

Adv Biophys

(1988)

T Kawase et al.

Lipid peroxidation and antioxidant defense systems in rat liver after chronic ethanol feeding

Hepatology

(1989)

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Citation Excerpt :
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^☆: Supported by grants from the Swedish Alcohol Research Fund and from the Swedish Medical Research Council, Stockholm, Sweden, and NIH-NIAAA 8116, Bethesda, MD.

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Modulation of experimental alcohol-induced liver disease by cytochrome P450 2E1 inhibitors☆

Abstract

Biochim Biophys Acta

Biochem Parmacol

Arch Biochem Biophys

Biochem Pharmacol

Biochem Pharmacol

J Biol Chem

Biochem Biophys Res Commun

Alcohol

Exp Mol Pathol

Alcohol

Alcohol

Alcohol

Toxicol Appl Pharmacol

Anal Biochem

J Mol Biol

J Biol Chem

Alcohol

Arch Biochem Biophys

Biochem Biophys Res Commun

Biochem Biophys Res Commun

Ethanol-induced lipid peroxidation: potentiation by long-term alcohol feeding and attenuation by methionine

J Lab Clin Med

Effect of prolonged alcohol administration on activities of various enzymes scavenging activated oxygen radicals and lipid peroxide level in the liver of rats

Biochem Pharmacol

Reactive free radical generation in vivo in heart and liver of ethanol-fed rats: correlation with radical formation in vitro

Lipid peroxidation dependent on ethanol-inducible cytochrome P-450 from rat liver

Adv Biophys

Lipid peroxidation and antioxidant defense systems in rat liver after chronic ethanol feeding

Hepatology