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

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 μ M. 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. the deviations of the key with significantly elevated The digital labels the fold change of the selected molecules

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