GENETIC DISORDERS OF
DRUG METABOLISM
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Ida
S. Owens, Ph.D.,
Principal Investigator Qi-Hui Gong, Ph.D., Research Fellow Nikhil Basu, Ph.D., Postdoctoral Fellow Shigeki Kubota, M.D., Postdoctoral Fellow Partha Mitra, Ph.D., Postdoctoral Fellow |
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The goal of the Section on Genetic Disorders of Drug Metabolism is to
understand the molecular genetics of the human UDP-glucuronosyltransferase
(UGT1) enzyme system, which is critical for removing from the body bilirubin
and other endogenous metabolites as well as a large and indeterminate
number of xenochemicals. To reach that goal, our studies focus on the
characterization of the multigenic UGT1 locus, which includes understanding
the regulation of certain isozymes; understanding the tissue distribution
and biochemical properties of the encoded isozymes; understanding the
phosphorylation requirement for UGTs and their participation in signaling
events; and purifying isozymes as models for structural analysis.
Figure 9 In addition, we studied the effect of glucuronidation on
the uptake of free drug and therapeutic efficacy. Given that the promising
immunosuppressant mycophenolic acid (MPA) has been introduced into tissue
transplantation protocols, we studied MPAs metabolism in greater
detail to understand rapid glucuronidation and its high dosage requirement.
We demonstrated that curcumin inhibits MPAs metabolism in both cell
culture and the mouse duodenum. Further, our in vivo studies show that
the coadministration of curcumin with MPA can transiently down-regulate
glucuronidation of MPA to increase its immunosuppressant effects by two-
to three-fold.
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PUBLICATIONS
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