Steven I. Shedlofsky, M.D.
Professor
College of Medicine
Phone:
(859) 281-4957
Fax:
(859) 281-4939
e-mail:
shedlof@uky.edu
|
Research Interests The
hepatic microsomal cytochromes P450 (P450s), capable of a broad range of mono-oxidations
for diverse substrates, help detoxify exogenous xenobiotics as well as metabolize
endogenous substrates. However, P450s can alto activate certain innocuous agents to
toxins. Currently, ten distinct P450 gene "families" have been identified in
various tissues of eukaryotes and most mammalian hepatic P450s belong to inducible
proteins with several mechanisms by which different isoforms are regulated. One aspect of
P450 regulation requiring more investigation is how Inflammation affects these
hepatic proteins. Previous studies in animal and more recent studies in human by our own
group have shown that the acute phase response elicited by gram negative bacterial
endotoxins (lipopolysaccharide, LPS) significantly alters hepatic P450 concentrations and
/or oxidative activities. We recently found that another inflammatory stimulus from
gram-positive bacterium, staphylococcal enterotoxin B (SEB), altered P450s in mice. These
changes are likely mediated by inflammatory cytokines such as TNF, IL-1, and IL-6. The aim
of our research is to further investigate the mechanisms by which the inflammatory
response affects specific hepatic cytochrome P450 isoforms. Studies in human volunteers
given the inflammatory stimulants endotoxin (lipopolysaccharide, LPS) and IL-6 will
investigate regulation of CYPs 3A4, 2D6 and 2E1 using the specific drug probes midazolam,
debrisoquine, and chlorzoxazone. Mice given LPS, SEB and various inflammatory cytokines
will be studied for gene expression specific protein concentrations, and drug metabolizing
activities.
Research Publications/presentations
Israel BC, Blouin RA, McIntyre W and Shedlofsky S: Effects of
interferon-a monotherapy on
hepatic drug metabolism in cancer patients. Brit J Clin Pharmacol 36:229-235, 1993.
Shedlofsky SI, Israel BC, McClain CJ, Hill DB and Blouin RA: Endotoxin
administration to humans inhibits hepatic cytochrome P450-mediated drug metabolism J
Clin Invest 94:2209-2214, 1994.
Gaetke LM, Shedlofsky SI, Talwalker RT and McClain CJ: Zinc metabolism
in human volunteers given endotoxin as a model of gram negative sepsis. (In press).
Shedlofsky SI, Israel BC and Blouin RA: Endotoxin-induced inflammation
depresses hepatic cytochrome P450-mediated drug metabolism in women. (Submitted).
Shedlofsky SI, Tosheva R , Snawder J: Depression of constitutive murine
cytochromes P450 by staphylococcal enterotoxin B. (Submitted). |
