Diabetes mellitus reduces activity of human UDP-glucuronosyltransferase 2B7 in liver and kidney leading to decreased formation of mycophenolic acid acyl-glucuronide metabolite.
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.
Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island 02881, USA.
Miroslav
M
Dostalek
Michael H
MH
Court
Suwagmani
S
Hazarika
Fatemeh
F
Akhlaghi
D000368:Aged; D003920:Diabetes Mellitus / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D005965:Glucuronates / Q000378:metabolism*; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D008861:Microsomes / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D000090264:UDP-Glucuronosyltransferase 1A9; D015215:Zidovudine / Q000031:analogs & derivatives / Q000378:metabolism; D000099148:UGT1A1 Enzyme
D005965:Glucuronates; D020719:Glucuronides; D014453:Glucuronosyltransferase; D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D012333:RNA, Messenger; D000090264:UDP-Glucuronosyltransferase 1A9; D015215:Zidovudine; D000099148:UGT1A1 Enzyme; C000715591:UGT1A9 protein, human; C491474:UGT2B7 protein, human