Ida Owens' Section on Genetic Disorders of Drug Metabolism studies UDP-glucuronosyltransferase (UGT) isozymes that detoxify numerous endogenous and exogenous chemical toxins/mutagens found in our daily diet and environment. Extending its earlier discovery that all UGTs require phosphorylation, the Section determined that UGT1A7 and UGT1A10 phosphorylations are ongoing processes, each mediated by PKCε and PKCα/δ signal transduction, respectively. Owens has shown that the UGT2B family isozymes UGT2B7 and UGT2B15, which detoxify endogenous genotoxic catechol estrogens and dysfunctional prostate–causing dihydrotestosterone (DHT), respectively, require tyrosine phosphorylation, with UGT2B15 also requiring serine/threonine phosphorylation. Src–tyrosine kinase phosphorylation of UGT2B7 is lost in breast tumors; UGT2B7 capacity to detoxify genotoxic catechol estrogens is dependent on active Src in these tissues. The Section found that curcumin reversibly downregulated UGT phosphorylation in antigen-stimulated mice such that, when treated with the immunosuppressant mycophenolic acid (MPA), which is widely used for renal transplant patients, the mice exhibited a substantial increase in both free circulating MPA and immunosuppression. Thus, glucuronidation can markedly compromise drug efficacy while transient downregulation of UGT phosphorylation can have a significant effect on the efficacy of glucuronidatable drugs.
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