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Role of kupffer cells in peroxisome proliferator-induced hepatocyte proliferation.

Authors
Rose-ML; Rusyn-I; Bojes-HK; Germolec-DR; Luster-M; Thurman-RG
Source
Drug Metab Rev 1999 Jan; 31(1):87-116
NIOSHTIC No.
20030713
Abstract
Peroxisome proliferators are a group of structurally diverse compounds that cause an increase in both the number and size of peroxisomes, elevale rates of cell proliferation, and cause liver cancer in rodents. Although the mechanism by which peroxisome proliferators cause tumors in rats and mice is not known, two hypotheses have been proposed. One view is that oxidative stress from peroxisomal oxygen metabolism is a critical event in the carcinogenic process, whereas others contend that elevated and sustained cell replication is responsible for the induction of tumors. In contrast to mitochondrial fatty acid Beta-oxidation, peroxisomal fatty acid Beta-oxidation produces H2O2. Peroxisome proliferators cause a disproportionate elevation in H202 due to the large increase in peroxisomal fatty acyl CoA oxidase with minimal induction of degradative enzymes such as catalase. The "oxidative stress" hypothesis proposed that excess H202 then diffuses out of the peroxisome and reacts with biological macromolecules such as DNA either directly or indirectly by generating several unstable oxygen species (e.g., superoxide anion and hydroxyl radical). In support of this theory, peroxisome proliferators generated 8-hydroxydeoxyguanosine (8OH-dO) adducts after treatment with ciprofibrate and lipofuscin accumulated following chronic exposure to phihalates. However, background levels of 8-0H-dG were high, making interpretation difficult. Moreover, increases in 8OH-dG adducts did not correlate well with the potency of the drug administered.
Keywords
Fatty-acids; Tumors; Lipids; Lipid-peroxidation; Peroxidases; Peroxides; Cellular-reactions; Cellular-function; Cell-growth; Cell-function; Proteins
CODEN
DMTRAR
Publication Date
19990101
Document Type
Journal Article
Fiscal Year
1999
NTIS Accession No.
NTIS Price
Issue of Publication
1
ISSN
0360-2532
NIOSH Division
HELD
Source Name
Drug Metabolism Reviews
State
WV; NC
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