Cytochrome [i]P[r]-4502E1: Its Physiological
and Pathological Role.
Lieber, Charles S.
Alcohol Research and Treatment
Center and Section of Liver Disease and Nutrition, Bronx Department of
Veterans Affairs Medical Center and Mount Sinai School of Medicine, Bronx,
New York.
APStracts 4:0001P, 1997.
ABSTRACT
The role of the microsomal ethanol-oxidizing system (MEOS) in hepatic
ethanol metabolism is reviewed, with focus on its constitutive, ethanol-inducible
cytochrome [i]P[r]-4502E1 (2E1). The MEOS was purified and reconstituted
using 2E1, phospholipids, and cytochrome [i]P[r]-450 reductase and shown
to oxidize ethanol to acetaldehyde, mainly as a monooxygenase and secondarily
via hydroxyl radicals, with transcriptional and posttranscriptional regulation.
Polymorphism of 2E1 was recognized, and enzymology (including cofactors,
role of lipids, inducers, and inhibitors) as well as cellular and tissue
distribution were chartered. Physiological functions involve lipid metabolism
and ketone utilization in starvation, obesity, and diabetes. The most significant
role of 2E1 is its adaptive response to high blood ethanol levels with
a corresponding acceleration of ethanol metabolism. The associated free
radical production, however, contributes to liver injury in the alcoholic.
Most importantly, 2E1 has a unique capacity to activate many xenobiotics
(85 of which are listed) to hepatotoxic or carcinogenic products. Induction
of induction also results in enhanced production of acetaldehyde, a highly
reactive and toxic metabolite. The proliferation of the endoplasmic reticulum
associated with 2E1 induction is also accompanied by enhanced activity
of other cytochrome [i]P[r]-450s, resulting in accelerated metabolism and
tolerance to other drugs, as well as increased degradation of retinol and
its hepatic depletion. Some substrates and metabolites, however, are innocuous
and may eventually be used as markers of heavy drinking. Recently discovered
effective 2E1 inhibitors also have great therapeutic potential.
APS Manuscript Number P24-6.
Article publication pending April 1997, Physiological Reviews.
ISSN 1080-4757 Copyright 1997 The American Physiological Society.
Published in APStracts on 5 February 1997