RT Journal Article
SR Electronic
T1 Inhibitory effects of endogenous linoleic acid and glutaric acid on the renal glucuronidation of berberrubine in mice and on recombinant human UGT1A7, 1AB, and 1A9
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.117.110668
DO 10.1124/mol.117.110668
A1 Na Yang
A1 Sijia Li
A1 Caixia Yan
A1 Runbin Sun
A1 Jun He
A1 Yuan Xie
A1 Ying Peng
A1 Guangji Wang
A1 Jiye Aa
YR 2018
UL http://molpharm.aspetjournals.org/content/early/2018/01/19/mol.117.110668.abstract
AB Berberrubine (BRB) has a strong lipid-lowering effect and can be extensively metabolized into berberrubine-9-O-β-D-glucuronide (BRBG) in vivo. Recently, pharmacokinetics studies showed that the production of BRBG was significantly decreased in the urine of mice fed with a high fat diet (HFD), indicating a decreased glucuronidation capacity. Based on the UGT isoform identification, hepatic and renal microsomal incubation, glucuronidation was examined to suggest the metabolism of BRB in liver and kidneys. The results showed that the renal UGT activity for metabolizing BRB markedly decreased, which may be highly related to the decreased expression and activity of renal Ugt1a7c. Surprisingly, in vitro studies revealed neither BRB nor BRBG inhibited the renal UGT activity. By employing an integrated strategy of metabolomics and pharmacokinetics, we identified and confirmed for the first time the inhibitory effect of some potential endogenous molecules on the renal glucuronidation of C57BL/6J mice, such as glutaric acid and linoleic acid. By employing recombinant human UGTs, we found that glutaric acid and linoleic acid efficiently affect the activity of recombinant human UGT1A7, 1A9 and 1A8 at their normal or abnormal physiological levels in vivo. Glutaric acid (2 mM) markedly inhibited the activity of UGT1A7 by 89.4% and UGT1A9 by 32.8%. The inhibition rates reached 99.3% for UGT1A9, 48.3% for UGT1A7, and 46.8% for UGT1A8 with linoleic acid at 200 μM. It has been suggested that the endogenous molecules have the potential to affect the efficiency of glucuronidation, which might be a key factor contributing to individual differences in drug metabolism.