UC Study Reevaluates Role of Enzyme
Published September 2003
Many drugs, pollutants and other environmental
chemicals are inert until they are metabolized (acted upon by enzymes)
to reactive intermediates that can bind to DNA, cause mutations, and
ultimately cancer. Results of a new study emphasize the importance of
studying the effects of pollutants such as 4-aminobiphenyl (ABP) in
live animals. ABP was formerly used in the dye and rubber industries
until it was found to cause bladder cancer in humans. Numerous previous
studies - in a test tube, chemical flask or in cell culture - have
shown that ABP is almost exclusively activated to reactive
intermediates by an enzyme called CYP1A2; these in-termediates bind to
DNA, which has been associated with the development of bladder cancer.
However, a new study in mice, which appeared in the August 20 edition
of the Journal of the National Cancer Institute, does not appear to
support this model.
Yutaka Tsuneoka, MD, PhD, former postdoctoral fellow of
the UC College of Medicine, and Daniel W. Nebert, MD, professor in the
UC Department of Environmental Health, found that mice with the
CYP1A2-producing gene "turned on" had not more (as expected) protection
from ABP intermediates, but less protection (after ABP treatment) than
similarly treated mice that do not have the CYP1A2-producing gene
turned on. The authors conclude that either CYP1A2 is not the major
enzyme that activates ABP in the intact animal or that other enzymes
metabolically activate ABP if the gene for CYP1A2 is absent.
"Our knockout mouse model has turned this theory on its head," said Dr. Nebert, "This further emphasizes the need and
the importance of lab animal studies."
Due to subtle differences in treatment (if the animal
inhales or ingests a chemical, or receives it by injection), and in the
target organ (whether the tissue is in direct contact with the chemical
or is in indirect contact only through the bloodstream), findings in
the intact animal can differ profoundly from studies performed only
outside the animal. According to Dr. Nebert, textbooks for more than 10
years have taught that CYP1A2 is necessary for the formation of ABP
reactive intermediates, but this fact has only been demonstrated in
test tubes and cells in culture.
"We expected that a mouse having the genetic absence of
CYP1A2 would be protected from ABP intermediates, compared with an
ABP-treated mouse having large amounts of CYP1A2, and we found just the
opposite," said Dr. Nebert. "We have two more exciting knockout mouse
models in our lab in which our findings also contradict previous dogma
that had been 'established' by experiments only outside the animal -
therefore providing strong reasons not to eliminate animal research
when studying human medical disease conditions."
Other authors for the study include Timothy P. Dalton,
PhD, assistant professor; Marian L. Miller, PhD, research associate
professor; Corey D. Clay, graduate student; Howard G. Shertzer, PhD,
professor; Glenn Talaska, PhD, associate professor; and Mario
Medvedovic, PhD, assistant professor, all from the UC Department of