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

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

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Lalwani, N. D. Fahl, W. E. Watanabe, T. Goel, S. K. Reddy, J. K.
Abstract	Several hypolipidemic drugs and certain industrial plasticizers induce proliferation of peroxisomes, enhance the activity of peroxisome-associated beta-oxidation of fatty acids, and produce hepatocellular carcinomas 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 genetic damage is introduced by the by-products of peroxisomal fatty acid beta-oxidation, an oxidative pathway that is dramatically increased in hypolipidemic drug-treated livers.
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	24
Volume Number	81
Language	English
Publisher	National Academy of Sciences
Publisher Date	1984-01-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	DNA, Viral Genetics Hydrogen Peroxide Metabolism Hypolipidemic Agents Toxicity Liver Microbodies Animals Kinetics Drug Effects Ultrastructure Microscopy, Electron Rats, Inbred F344 Simian Virus 40 Research Support, U.S. Gov't, P.H.S. Multidisciplinary
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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