Abstract
Mammalian UDP-glucuronosyltransferase (UGT) isozymes detoxify a vast number of critical drugs, toxins, dietary constituents, and environmental chemicals by conjugation with glucuronic acid. Because UGTs are endoplasmic reticulum-bound making purification and biochemical analyses difficult, the mechanism of UGT conversion of innumerable chemicals is not understood. Recently, we uncovered that UGT isozymes require phosphorylation for activity. Phosphorylation, regulated via signaling, occurs on both serine/threonine and tyrosine residues. PKC phosphorylation is shown to determine substrate specificity of a human UGT isozyme; Src tyrosine kinase phosphorylation of another UGT is shown to control detoxification of catechol estrogens, linked to breast cancer. Moreover, we have evidence that UGT phosphorylation can be targeted transiently to reduce premature clearance of therapeutic drugs (e.g mycophenolic acid), suggesting inhibition of glucuronidation can greatly improve efficacy.
Published Version
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