© 1998 by Oxford University Press
Journal Of The National Cancer Institute, Vol 90, 1702-1709, Copyright © 1998 by Oxford University Press
FJ Gonzalez, JM Peters and RC Cattley
Peroxisome proliferators are a diverse group of chemicals that include
several therapeutically used drugs (e.g., hypolipidemic agents),
plasticizers and organic solvents used in the chemical industry,
herbicides, and naturally occurring hormones. As the name implies,
peroxisome proliferators cause an increase in the number and size of
peroxisomes in the liver, kidney, and heart tissue of susceptible species,
such as rats and mice. Long-term administration of peroxisome proliferators
can cause liver cancer in these animals, a response that has been the
central issue of research on peroxisome proliferators for many years.
Peroxisome proliferators are representative of the class of nongenotoxic
carcinogens that cause cancer through mechanisms that do not involve direct
DNA damage. The fact that humans are frequently exposed to these agents
makes them of particular concern to government regulatory agencies
responsible for assuring human safety. Whether frequent exposure to
peroxisome proliferators represents a hazard to humans is unknown; however,
increased cancer risk has not been shown to be associated with long-term
therapeutic administration of the hypolipidemic drugs gemfibrozil,
fenofibrate, and clofibrate. To make sound judgments regarding the safety
of peroxisome proliferators, the validity of extrapolating results from
rodent bioassays to humans must be based on the agents' mechanism of action
and species differences in biologic activity and carcinogenicity. The
peroxisome proliferator- activated receptor alpha (PPARalpha), a member of
the nuclear receptor superfamily, has been found to mediate the activity of
peroxisome proliferators in mice. Gene-knockout mice lacking PPARalpha are
refractory to peroxisome proliferation and peroxisome proliferator- induced
changes in gene expression. Furthermore, PPARalpha-null mice are resistant
to hepatocarcinogenesis when fed a diet containing a potent nongenotoxic
carcinogen WY-14,643. Recent studies have revealed that humans have
considerably lower levels of PPARalpha in liver than rodents, and this
difference may, in part, explain the species differences in the
carcinogenic response to peroxisome proliferators.
REVIEWS
Mechanism of action of the nongenotoxic peroxisome proliferators: role of the peroxisome proliferator-activator receptor alpha
National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. fjgonz@helix.nih.gov
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