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    • Hepatic drug metabolizing enzymes and

    2022-09-09

    Hepatic drug-metabolizing JQ1 and transporters expression were regulated by nuclear receptors [19], [20], [21]. The effects of HFD-induced fatty liver on drug metabolizing enzymes in mice were recently studied, and the results provided a systematic evaluation of the changes of nuclear receptors and their downstream xenobiotic metabolism enzymes induced by the HFD [22]. In this study, we also detected the expression of related nuclear receptors. The mRNA expression of Hnf4α, LXRα and FXR were decreased, while CAR and PPARγ were increased in the liver of obese rats compared to those in normal rats. Therefore, the deviation of enzymes and transporter in the liver of obese rats may be due to changes of these nuclear receptors. In the present study, significant reduction of Cyp3a1 mRNA expression was observed in the liver of obese rats, and the protein expression level in the liver was consistent with mRNA expression. In contrast, Cyp3a2 mRNA and protein expression level were not changed. Furthermore, CYP3A1/2 activity determined using midazolam, a CYP3A probe substrate, was also not changed between normal rats and high-fat diet induced obese rats. However, the clearance of CYP3A4 substrates lfentanyl, alprazolam, docetaxel, trazodone, midazolam, carbamazepine, N-methyl-erythromycin, ciclosporin, triazolam and taranabant was significantly lower in obese humans [4], [11]. The discrepancy may be due to species difference in CYP3A expression. Based on the data of this study, the activity of CYP3A4 may be reduced in obese humans. Further studies should be carried out in humans, especially the precise regulatory mechanism of obese on CYP3A4. CYP1A2 contributes to about 5% of phase I drug metabolism in humans [23]. Phenacetin, caffeine and theophylline have been identified as CYP1A2 specific probes [24], [25], [26]. Previous studies reported that Cyp1a2 RNA levels was not changed by high fat feeding in mice [27], but our observations are consistent with Oh et al, who reported that Cyp1a2 gene expression was reduced [28]. In addition, caffeine clearance was not changed between non-obese and obese human and between obese human before and after weight loss [29]. Species, gender and dietary differences could be influence factors of phase I enzymes level with regard to obesity and its associated diabetes and fatty liver disease. Consistent with the previous studies that Cyp2b10 gene expression was reduced in ob/ob and high-fat diet mice [27], data from this study also showed that mRNA levels of Cyp2b1 was decreased dramatically in obese rats. In addition, our findings revealed that Cyp2c11 and Cyp4a1 levels were decreased in high-fat diet induced obese rats compared to normal rats. In contrast, a significant increase of Cyp2b and Cyp4a levels was found in db/db mice [13]. Differences in genetically engineered and diet-induced animal models of obesity may result in these differences. Interesting, other Cyp2d1/2, Cyp2j3 and Cyp2e1 mRNA expression did not differ in the liver of between obese and normal rats. Last but not least, flavin monooxygenases as important phase I enzymes play a key role in the catabolism of natural and artificial compounds [30]. In our results, fmo1 gene expression level was reduced, while fmo3 was not differences in the liver of obese rats and normal rats. In hepatic phase II enzymes, the mRNA expression of Ugt1a1, Ugt1a3, Ugt1a6, Ugt1a9, Ugt2b7, Nat1, and Gstt1, were lower in diet-induced obese rats compared to these of control rats. The activity of hepatic UGT1A1, 1A3, 1A6, 1A9, and 2B7 was significantly decreased in obese rats by hepatic microsomal incubation in vitro, which should be verified in vivo using the appropriate probes in the future work. UGT enzymes catalyze the conjugation of various exogenous compounds and endogenous substances, and are involved in about 50% of phase II drug metabolism in humans [31]. Their substances are conjugated to polar compounds to more easily eliminate. Our data showed that diet-induced obese significantly decreased most of phase II enzyme, implying part of phase II substrates metabolism may slow in an obese individual. Hepatic transporters anchor in polarized hepatocytes, and transport molecules between sinusoidal blood, biliary canaliculus and hepatocytes [32]. Nonalcoholic steatohepatitis may influence the expression and function of hepatic transporters. In this study, it is found that the mRNA expression of Slco1a2, Slc22a5, Abcc2, Abcc3, Abcb1a, and Abcg2 were reduced, but Abcb1b levels was dramatically increased in the liver of HFD group compared to LFD group. These changes may be considered to predict drug disposition and develop optimal drug dosage regimens in obese patients.