DNA damage related to increased hydrogen peroxide generation by hypolipidemic drug-induced liver peroxisomes

W. E. Fahl, N. D. Lalwani, T. Watanabe, S. K. Goel, J. K. Reddy

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Abstract

Several hypolipidemic drugs and certain industrial plasticizers induce proliferation of peroxisomes, enhance the activity of peroxisome-associated β-oxidation of fatty acids, and produce hepatocellular carcinoma in the livers of rodents. Because these chemicals themselves are not mutagens and do not covalently modify DNA, unlike the majority of chemical carcinogens, we proposed that the persistent proliferation of peroxisomes, and the induction of associated peroxisomal oxidases, caused a sustained increase in intracellular H2O2 or other reduced oxygen species, which would then introduce mutagenic DNA damage. In the present study, we investigated the ability of peroxisomes purified from the livers of normal and hypolipidemic drug-treated rats to induce DNA strand scission in vitro. Gradient-purified peroxisomes from livers of hypolipidemic drug treated rats produced a 30- to 70-fold increase in H2O2 generation when compared to controls. The levels of H2O2 generated in incubations containing control or hypolipidemic drug-induced peroxisomes correlated well with the induction of single strand breaks in supercoiled simian virus 40 DNA molecules that were included in these reconstituted peroxisome incubations. Addition of excess catalase to peroxisome incubations failed to prevent strand breaks, suggesting that other reduced oxygen species may be rapidly generated from H2O2. These experimental results are consistent with a mechanism of hepatocarcinogenesis in which hepatocellular damage is introduced by the by-products of peroxisomal fatty acid β-oxidation, an oxidative pathway that is dramatically increased in hypolipidemic drug-treated livers.

Original languageEnglish (US)
Pages (from-to)7827-7830
Number of pages4
JournalProceedings of the National Academy of Sciences of the United States of America
Volume81
Issue number24 I
DOIs
StatePublished - Dec 1 1984

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