Evidence that unsaturated fatty acids are potent inhibitors of renal UDP-glucuronosyltransferases (UGT): kinetic studies using human kidney cortical microsomes and recombinant UGT1A9 and UGT2B7

摘要: Renal ischaemia is associated with accumulation of fatty acids (FA) and mobilisation arachidonic acid (AA). Given the capacity UDP-glucuronosyltransferase (UGT) isoforms to metabolise both drugs FA, we hypothesised that FA would inhibit renal drug glucuronidation. The effect (C2:0-C20:5) on 4-methylumbelliferone (4-MU) glucuronidation was investigated using human kidney cortical microsomes (HKCM) recombinant UGT1A9 UGT2B7 as enzyme sources. 4-MU exhibited Michaelis-Menten kinetics HKCM (apparent K(m) (K(m)(app)) 20.3 microM), weak substrate inhibition (K(m)(app) 10.2 microM, K(si) 289.6 sigmoid (S(50)(app)440.6 microM) Similarly, biphasic UDP-glucuronic (UDPGA) were observed (S(50) 354.3 88.2 microM). In contrast, for UDPGA 493.2 suggested kinetic interactions UGTs specific xenobiotic co-substrate (UDPGA). (C16:1-C20:5) significantly inhibited (25-93%) HKCM, or catalysed Although linoleic (LA) AA competitive inhibitors by (K(i)(app) 6.34 0.15 respectively), only LA a inhibitor 4.06 atypical kinetics. These data indicate are potent UGT2B7. It conceivable therefore during periods may impair thus compromising protective against drug-induced nephrotoxicity.