Selectivity for inhibition of nilotinib on the catalytic activity of human UDP-glucuronosyltransferases.
1. Nilotinib, a tyrosine kinase inhibitor, could potently inhibit SN-38 glucuronidation mainly catalyzed by UDP-glucuronosyltransferase (UGT) 1A1. This study was designed to investigate whether nilotinib can be used as a selective inhibitor of UGT1A1 in human liver. 2. Assays with recombinant UGTs indicated that nilotinib could strongly inhibit the activity of UGT1A1 and decreased the activity of extra-hepatic UGT1A7 to a much lesser extent. The inhibition on 4-methylumbelliferone (4Mu) glucuronidation by recombinant UGT1A1 obeyed competitive inhibition mechanism, with a kinetic constants (Ki) value of 0.17 μM. Assays with human liver microsomes (HLM) demonstrated that nilotinib could selectively inhibit estradiol-3-O-glucuronidation (E2-3-O-glucuronidation), a probe reaction of UGT1A1. Kinetic studies displayed that the inhibition on E2-3-O-glucuronidation followed non-competitive inhibition model, different from the inhibition on 4Mu glucuronidation. The Ki values were calculated to be 0.14 and 0.53 μM, depending on the enzyme sources of recombinant UGT1A1 or HLM, respectively. 3. Given that UGT1A7 is an extra-hepatic enzyme, this study indicates that nilotinib can be used as a selective inhibitor of UGT1A1 in human liver.
Department of Hematology, The First Affiliated Hospital of Liaoning Medical University , Jinzhou , China .
Limei
L
Ai
Liangliang
L
Zhu
Lu
L
Yang
Guangbo
G
Ge
Yunfeng
Y
Cao
Yong
Y
Liu
Zhongze
Z
Fang
Yanyan
Y
Zhang
D002384:Catalysis; D004791:Enzyme Inhibitors / Q000737:chemistry*; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000187:drug effects; D008862:Microsomes, Liver / Q000378:metabolism; D010641:Phenotype; D011743:Pyrimidines / Q000737:chemistry*; D011994:Recombinant Proteins / Q000378:metabolism; D000099148:UGT1A1 Enzyme
D004791:Enzyme Inhibitors; D020719:Glucuronides; D014453:Glucuronosyltransferase; D011743:Pyrimidines; D011994:Recombinant Proteins; D000099148:UGT1A1 Enzyme; C524630:UGT1A7 protein, human; C498826:nilotinib