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¹Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, USA. zhugejian@yahoo.com

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Summary

Lowering S-adenosyl-L-methionine (SAM) sensitizes liver cells to arachidonic acid (AA) toxicity, especially when cytochrome P450 2E1 (CYP2E1) is high. This interaction, involving reactive oxygen species and lipid peroxidation, may contribute to alcohol-induced liver injury.

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Area of Science:

Hepatology
Biochemistry
Toxicology

Background:

High cytochrome P450 2E1 (CYP2E1) levels in hepatocytes increase toxicity from arachidonic acid (AA) or reduced S-adenosyl-L-methionine (SAM).
Pyrazole treatment induces CYP2E1, while cycloleucine inhibits methionine adenosyltransferase (MAT), lowering SAM levels.

Purpose of the Study:

To investigate if decreased SAM sensitizes hepatocytes to AA toxicity, particularly in CYP2E1-enriched cells.
To elucidate the mechanisms underlying AA-induced hepatotoxicity in the context of altered SAM levels and CYP2E1 expression.

Main Methods:

Hepatocytes from pyrazole- or saline-treated rats were used.
Cells were treated with cycloleucine (to lower SAM) and/or arachidonic acid (AA).
Toxicity, apoptosis, reactive oxygen species (ROS) production, and lipid peroxidation were measured. Protective effects of SAM, trolox, and trifluoperazine were assessed.

Main Results:

Pyrazole-treated hepatocytes had 50% lower SAM levels.
Combined cycloleucine and AA treatment increased toxicity and apoptosis in pyrazole-treated hepatocytes compared to controls.
Cytotoxicity was mitigated by SAM, trolox, and trifluoperazine, and by in vivo treatment with chlormethiazole (a CYP2E1 inhibitor).
AA treatment elevated ROS and lipid peroxidation more in pyrazole-treated hepatocytes.

Conclusions:

Reduced SAM levels potentiate AA-induced oxidative stress and lipid peroxidation in CYP2E1-enriched hepatocytes.
This interaction, involving CYP2E1 induction, decreased SAM, and polyunsaturated fatty acid-induced lipid peroxidation, may contribute to alcohol-induced liver injury.