Mechanism of tissue injury induced by drugs or other xenobiotics; mechanisms
by which one chemical modulates the toxicity of another; carcinogenesis,
human metabolism of environmental pollutants.
Dr. Sipes' research activities center around the disposition
and metabolism of environmental chemicals. He is particularly
interested in how various chemicals are metabolized to toxic metabolites
that damage the liver and ovary, as well as other tissues.
It is often a metabolite of chemical that it responsible for the
tissue injury produced by exposure to the chemical. Species
differences in the metabolism of the chemical (i.e. rate of route)
may explain why one species is susceptible and another is resistant
to the toxic effects of the chemical. Of particular interest
is understanding how humans metabolize a chemical.
More recently, Dr. Sipes and his colleagues have shown how the
Kupffer cells, the resident macrophage in the liver, play a major
role in the progression of chemical-induced liver injury.
Kupffer cell function modulation provides an opportunity to affect
the progression of hepatic injury.
Examples of the research projects currently are: 1) determining
why female mice, but not rats develop ovarian tumors upon exposure
to 4-vinylcyclohexene, butadiene and isoprene. Data generated
to date suggest female mice produce a toxic metabolite at a much
greater rate than rats; 2) understanding the role of the immune
system in the hepatotoxicity and pulmonary toxicity of drugs and
environmental chemicals; 3) understanding how one chemical influences
the toxicity of another, i.e. "interactive hepatotoxicity".
Ishiyama, H., Hoglen, N.C., and Sipes, I.G.: Diethyldithiocarbamate
enhances production of nitric oxide and TNF-a by lipopolysaccharide-stimulated
rat Kupffer cells. Toxicol. Sci., 55:206-214, 2000.
Younis, H.S., Holgen, N.C., Kuester, R.K., Gunawardhana, L.,
and Sipes, I.G.: 1,2-Dichlorobenzene mediated hepatocellular oxidative
stress in Fischer-344 and Sprague-Dawley rats. Toxicol. Appl.
Pharmacol., 163:141-148, 2000.
Burkey, J.L., Sauer, J-M., McQueen, C.A., and Sipes, I.G.: Cytotoxicity
and genotoxicity of methyleugenol and related congeners - a mechanism
of activation for methyleugenol. Mutation Res., 453:25-33, 2000.
Borman, S.M., VanDePol, B.J., Kao, S., Thompson, K.E., Sipes,
I.G., and Hoyer, P.B.: A single dose of the ovotoxicant, 4-vinylcyclohexene
diepoxide, protects against atresia in rat small ovarian follicles.
Toxicol. Appl. Pharmacol., 158:244-252, 1999.
Firriolo, J.M., Ayala-Fierro, F., Sipes, I.G., and Carter, D.E.:
Absorption and disposition of cobalt naphthenate in rats after
a single oral dose. J. Toxicol. Environ. Health, 58:383-395, 1999.
Abril, E.R., Thorne, P.A., Waite, S.I., Holubec, H., Nelson,
M., Sipes, I.G., Lantz, R.C., McCuskey, R.S., and Earnest, D.L.:
Binge-type ethanol consumption causes induction of Kupffer cell
cytochrome P4502E1, increased intracellular reactive oxygen species
and prolonged extracellular release of superoxide after blood
alcohol normalizes. Cells of Hepatic Sinusoid, 99-100, 1999.
Halladay, J.S., Sauer, J.-M., and Sipes, I.G.: Metabolism and
disposition of [14C]1- nitronaphthalene in male
Sprague-Dawley rats. Drug Metab. Dispos., 27:1456-1465, 1999.
