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Abstract

Cytotoxicity of acetaminophen in human cytochrome P4502E1-transfected HepG2 cells.

Y Dai and A I Cederbaum
Journal of Pharmacology and Experimental Therapeutics June 1995, 273 (3) 1497-1505;
Y Dai
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A I Cederbaum
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Abstract

Acetaminophen (APAP) when administered in excess can cause severe hepatic necrosis in vivo. To study the mechanism of APAP toxicity and the role of cytochrome P450, a previously established human hepatoma HepG2 subline, MVh2E1-9, that constitutively expresses human CYP2E1 was used as a model. At high concentrations (above 5 mM) and when intracellular reduced glutathione (GSH) was depleted, APAP caused severe cytotoxicity in MVh2E1-9, but not in MV-5 cells which lack CYP2E1. The APAP cytotoxicity was dependent on the concentration of APAP and time of exposure, and could be blocked by 4-methylpyrazole, ethanol, diallyl sulfide, N-acetylcysteine and N-t-butyl-alpha-phenylnitrone, but not by propylgallate, an inhibitor of lipid peroxidation. Significantly more 14C-labeled APAP protein adduct was detected in MVh2E1-9 cells than MV-5 cells, especially after depletion of GSH. The formation of the APAP adducts could be inhibited by the same agents which prevent APAP cytotoxicity. At a lower concentration (1-2 mM), APAP inhibited proliferation in both MVh2E1-9 and the control MV-5 cells to similar extents. This antiproliferative action of APAP did not require depletion of GSH as did the cytotoxic action of APAP. These data suggest that APAP has a dual toxic effect on MVh2E1-9 cells: a P450-independent antiproliferative effect and the CYP2E1-dependent cytotoxic effect. These results demonstrate the ability of human CYP2E1 to activate APAP to reactive metabolites which form covalent protein adducts and cause toxicity to a hepatoma cell line.

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Journal of Pharmacology and Experimental Therapeutics
Vol. 273, Issue 3
1 Jun 1995
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Abstract

Cytotoxicity of acetaminophen in human cytochrome P4502E1-transfected HepG2 cells.

Y Dai and A I Cederbaum
Journal of Pharmacology and Experimental Therapeutics June 1, 1995, 273 (3) 1497-1505;

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Abstract

Cytotoxicity of acetaminophen in human cytochrome P4502E1-transfected HepG2 cells.

Y Dai and A I Cederbaum
Journal of Pharmacology and Experimental Therapeutics June 1, 1995, 273 (3) 1497-1505;
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