Modulation of UDP-glucuronosyltransferase activity by protein-protein association

Abstract

Drug oxidation and conjugation mediated by cytochrome P450 (P450) and UDP-glucuronosyltransferase (UGT) have long been considered to take place separately. However, our recent studies have suggested that CYP3A4 specifically associates with UGT2B7 and alters the regioselectivity of morphine glucuronidation. This observation strongly supports the view that there is functional cooperation between P450 and UGT to facilitate multistep drug metabolism. In recent years, accumulating evidence has suggested an interaction between UGT isoforms or between P450 and UGTs and a change in UGT function by protein-protein association. In this review, we summarize these interactions and discuss their relevance to UGT function.

Keywords::

• Protein-protein interaction
• glucuronidation
• UDP-glucuronosyltransferase
• cytochrome P450
• drug metabolism

Acknowledgements

Part of our work quoted in this review was supported by the Grants-in-Aid for the Scientific Research by Ministry of Science, Education and Sports in Japan (recipients: YI, HY). The authors are grateful to collaborators; Dr. Peter I. Mackenzie in Flinders Medical Centre and School of Medicine, Flinders University of South Australia, Adelaide, Australia; Dr. Y. Yamazoe in Graduate School of Tohoku University, Sendai, Japan; Dr. K. Nagata in Tohoku Pharmaceutical University; Sendai, Japan: Dr. S. Ikushiro in Toyama Prefectural University (Imizu, Japan); Dr. S. Ohgiya in National Institute of Advanced Industrial Science and Technology (Tsukuba, Japan). The authors are also very grateful for the excellent assistance by graduate and undergraduate students involved in this study. Finally, the authors express deepest sympathy to our mentor, the late Dr. Kazuta Oguri.

Declaration of interest: The author reports no financial conflicts of interest. The author is responsible for the content and writing of this paper.