Diet-induced obese alters the expression and function of hepatic drug-metabolizing enzymes and transporters in rats

Zhang, Lei; Xu, Peipei; Cheng, Yi; Wang, Peili; Ma, Xinrun; Liu, Mingyao; Wang, Xin; Xu, Feng

doi:10.1016/j.bcp.2019.05.002

Cited by 31 publications

(20 citation statements)

References 31 publications

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“…Two isoforms of MDR1/P-glycoprotein have been described for rodents, encoded by genes Mdr1a (Abcb1a) and Mdr1b (Abcb1b), and under certain circumstances they have been shown to play dissimilar functions in different organs or to respond differently to the same stimulus (Koehn et al, 2019;Su et al, 2017;Zhang et al, 2019). In our study, only Mdr1b RNA was affected by the AsIII treatment, whereas Mdr1a remained unchanged.…”

Section: Discussionsupporting

confidence: 47%

Effects of oral exposure to arsenite on arsenic metabolism and transport in rat kidney

et al. 2020

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Section: Discussionsupporting

confidence: 47%

Effects of oral exposure to arsenite on arsenic metabolism and transport in rat kidney

et al. 2020

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“…The two experiments consistently demonstrated that the metabolic function of CYP1A2 in KO rats was significantly deficient. In addition, the changes of physiological state of rats may affect the treatment of drugs (Zhang et al, 2019). Therefore, we speculate that abnormal lipid metabolism in CYP1A2 KO rats may also affect the metabolic capacity or drug transport capacity, leading to changes in the pharmacokinetic behavior and parameters of the probe substrate.…”

Section: Discussionmentioning

confidence: 96%

Characterization of a Novel CYP1A2 Knockout Rat Model Constructed by CRISPR/Cas9

Sun

Zhang

et al. 2021

Drug Metab Dispos

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Cytochrome P450 1A2 (CYP1A2) as one of the most important CYP isoforms is involved in the biotransformation of many important endogenous and exogenous substances. CYP1A2 also plays an important role in the development of many diseases because it is involved in the biotransformation of precancerous substances and poisons. Although the generation of Cyp1a2 knockout (KO) mouse model has been reported, there are still no relevant rat models for the study of CYP1A2-mediated pharmacokinetics and diseases. In this report, CYP1A2 KO rat model was established successfully by CRISPR/Cas9 without any detectable off-target effect. Compared with wild-type rats, this model showed a loss of CYP1A2 protein expression in the liver. The results of pharmacokinetics in vivo and incubation in vitro of specific substrates of CYP1A2 confirmed the lack of function of CYP1A2 in KO rats. In further studies of potential compensatory effects, we found that CYP1A1 was significantly up-regulated, and CYP2E1, CYP3A2 and LXRβ were down-regulated in KO rats. In addition, CYP1A2 KO rats exhibited a significant increase in serum cholesterol and free testosterone, accompanied by mild liver damage and lipid deposition, suggesting that CYP1A2 deficiency affects lipid metabolism and liver function to a certain extent. In summary, we successfully constructed the CYP1A2 KO rat model, which provides a useful tool for studying the metabolic function and physiological function of CYP1A2.

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“…A similar study has investigated the high fat diet effect on rats hepatic DMPK system at the transcriptional level [42]. In a 12-weeks treatment by using high fat diet, a couple mice hepatic phase I and phase II metabolic enzymes as well as some transporters were down-regulated at the transcriptional level.…”

Section: Discussionmentioning

confidence: 99%

High fat diet significantly changed the global gene expression profile involved in hepatic drug metabolism and pharmacokinetic system in mice

Yang

et al. 2020

Nutr Metab (Lond)

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Background: High fat diet impact transcription of hepatic genes responsible for drug metabolism and pharmacokinetics. Until now, researches just focused on a couple specific genes without a global profile showing. Age-dependent manner was also not noted well. This study aims to investigate the high fat diet effect on transcriptome of drug metabolism and pharmacokinetic system in mouse livers and show the age-dependent evidence. Methods: C57BL/6 male mice were used in this experiment. High fat diet was used to treat mice for 16 and 38 weeks. Serum total cholesterol, low density lipoprotein cholesterol, aspartate transaminase, and alanine transaminaselevels were measured. Meanwhile, Histology, RNA-Seq, RT-PCR analysis and fourteen major hepatic bile acids quantification were performed for the liver tissues. Data was mined at levels of genes, drug metabolism and pharmacokinetic sysem, and genome wide. Results: Treatment with high fat diet for 38 weeks significantly increased levels of serum lipids as well as aspartate transaminase, and alanine transaminase. Meanwhile, lipid accumulation in livers was observed. At week 38 of the experiment, the profile of 612 genes involved in drug metabolism and pharmacokinetics was significantly changed, indicated by a heatmap visulization and a principal component analysis. In total 210 genes were significantly regulated. Cyp3a11, Cyp4a10, and Cyp4a14 were down-regulated by 10-35 folds, while these three genes also were highly expressed in the liver. High fat diet regulated 11% of genome-wide gene while 30% of genes involved in the hepatic drug metabolism and pharmacokinetic system. Genes, including Adh4,

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Diet-induced obese alters the expression and function of hepatic drug-metabolizing enzymes and transporters in rats

Cited by 31 publications

References 31 publications

Effects of oral exposure to arsenite on arsenic metabolism and transport in rat kidney

Effects of oral exposure to arsenite on arsenic metabolism and transport in rat kidney

Characterization of a Novel CYP1A2 Knockout Rat Model Constructed by CRISPR/Cas9

High fat diet significantly changed the global gene expression profile involved in hepatic drug metabolism and pharmacokinetic system in mice

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