Abstract
Mycophenolic acid (MPA) is an immunosuppressive agent commonly used after organ transplantation. Altered concentrations of MPA metabolites have been reported in diabetic kidney transplant recipients, although the reason for this difference is unknown. We aimed to compare MPA biotransformation and UDP-glucuronosyltransferase (UGT) expression and activity between liver (n = 16) and kidney (n = 8) from diabetic and nondiabetic donors. Glucuronidation of MPA, as well as the expression and probe substrate activity of UGTs primarily responsible for MPA phenol glucuronide (MPAG) formation (UGT1A1 and UGT1A9), and MPA acyl glucuronide (AcMPAG) formation (UGT2B7), was characterized. We have found that both diabetic and nondiabetic human liver microsomes and kidney microsomes formed MPAG with similar efficiency; however, AcMPAG formation was significantly lower in diabetic samples. This finding is supported by markedly lower glucuronidation of the UGT2B7 probe zidovudine, UGT2B7 protein, and UGT2B7 mRNA in diabetic tissues. UGT genetic polymorphism did not explain this difference because UGT2B7*2 or *1c genotype were not associated with altered microsomal UGT2B7 protein levels or AcMPAG formation. Furthermore, mRNA expression and probe activities for UGT1A1 or UGT1A9, both forming MPAG but not AcMPAG, were comparable between diabetic and nondiabetic tissues, suggesting the effect may be specific to UGT2B7-mediated AcMPAG formation. These findings suggest that diabetes mellitus is associated with significantly reduced UGT2B7 mRNA expression, protein level, and enzymatic activity of human liver and kidney, explaining in part the relatively low circulating concentrations of AcMPAG in diabetic patients.
Footnotes
This work was supported in part by the National Institutes of Health National Institute of General Medical Sciences [Grant R01-GM061834] (to M.H.C.); the American Heart Association [Grant 0855761D] (to F.A.); and an investigator initiated grant from Novartis Pharmaceuticals (to F.A.). The RI-INBRE core facility used in this study was funded by the National Institutes of Health National Center for Research Resources [Grant P20-RR016457].
The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding organizations.
The authors indicate no potential conflict of interest exists with any commercial entity whose products are described in the manuscript.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.036608.
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ABBREVIATIONS:
- MPA
- mycophenolic acid
- MPAG
- pharmacologically inactive phenolic 7-O-glucuronide of MPA
- AcMPAG
- pharmacologically active acyl glucuronide of MPA
- GI
- gastrointestinal
- UGT
- uridine diphosphate-glucuronosyltransferase
- HEK
- human embryonic kidney
- AZT
- zidovudine
- HPLC
- high-performance liquid chromatography
- HLM
- human liver microsome
- HKM
- human kidney microsome
- PCR
- polymerase chain reaction
- TBARS
- thiobarbituric acid reactive substance.
- Received October 2, 2010.
- Accepted December 1, 2010.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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