Hepatic expression of cytochrome P450 in type 2 diabetic Goto–Kakizaki rats

Oh, Soo Jin; Choi, Jong Min; Yun, Kang Uk; Oh, Jung Min; Kwak, Hui Chan; Oh, Jin-Gyo; Lee, Kye Sook; Kim, Bong-Hee; Heo, Tae‐Hwe; Kim, Sang Kyum

doi:10.1016/j.cbi.2011.12.010

Cited by 36 publications

(16 citation statements)

References 26 publications

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“…In our type 2 diabetes rat model, no significant differences of hepatic Cyp2c11 expression was found between male obese (diabetic) and lean (non-diabetic) ZSF1 rats. The difference between published and our results seems to be based on the type of diabetes model, because similarly no significant diabetesinduced changes of hepatic Cyp2c11 gene expression was identified in ZDF rats or Goto-Kakizaki rats, two other established type 2 diabetes rat models [42,43].…”

Section: Discussioncontrasting

confidence: 50%

Next generation sequencing of sex-specific genes in the livers of obese ZSF1 rats

et al. 2015

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Type 2 diabetes induces pathophysiological changes in the liver. The aim of this study was to identify differently expressed genes in the livers of male and female ZSF1 rats (ZDFxSHHF-hybrid, generation F1), a model for type 2 diabetes. Gene expression was investigated using next-generation sequencing (NGS). Selected candidate genes were verified by real-time PCR in the livers of obese and lean rats. 103 sex-different genes, associated to pathways "response to chemical stimulus", "lipid metabolism", and "response to organic substance", were identified. Male-specific genes were involved in hepatic metabolism, detoxification, and secretion, e.g. cytochrome P450 2c11 (Cyp2c11), Cyp4a2, glutathione S-transferases mu 2 (Gstm2), and Slc22a8 (organic anion transporter 3, Oat3). Most female-specific genes were associated to lipid metabolism (e.g. glycerol-3-phosphate acyltransferase 1, Gpam) or glycolysis (e.g. glucokinase, Gck). Our data suggest the necessity to pay attention to sex- and diabetes-dependent changes in pre-clinical testing of hepatic metabolized and secreted drugs.

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Section: Discussioncontrasting

confidence: 50%

Next generation sequencing of sex-specific genes in the livers of obese ZSF1 rats

et al. 2015

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“…Besides fatty acid, there are many other abnormal factors in diabetic serum such as ketone body and hormones (growth hormone and testosterone levels). It has been reported that ketone body increased the expression of CYP2B in primary cultured rat hepatocytes (44), and the elevation of ketone body plays a critical role in the upregulation of hepatic CYP2E1 in diabetic rats (45). Impaired secretion of growth hormone in diabetic rats was also responsible for the regulation of CYP450.…”

Section: Discussionmentioning

confidence: 94%

Increased Levels of Fatty Acids Contributed to Induction of Hepatic CYP3A4 Activity Induced by Diabetes — In Vitro Evidence From HepG2 Cell and Fa2N-4 Cell Lines

Duan

et al. 2014

J Pharmacol Sci

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Abstract.Accumulating evidences have shown that diabetes upregulated the function and expression of CYP3A4, but the mechanism remained unclear. In this study, HepG2 cells were incubated with serum from diabetic rats induced by streptozotocin, and the activity of CYP3A4 was measured by substrate metabolism. Results showed that incubation with diabetic serum significantly induced CYP3A4 activity in HepG2 cells. To identify the specific factors contribut ing to the regulation, the abnormally altered components in diabetic serum, including glucose, insulin, cholesterol, and free fatty acids were screened. It was found that only fatty acids concen trationdependently upregulated CYP3A4 activity, and the induction by fatty acids was further confirmed in Fa2N4 cells. Data from western blotting and QTPCR showed that induction of CYP3A4 activity was associated with upregulation of CYP3A4 protein and mRNA levels. In addition, effects of pharmacological inhibitors on fatty acid-induced CYP3A4 activity were studied. The results indicated that the induction of CYP3A4 activity by oleic acid may be partly via AMPK, PKC, and NFkB-dependent pathways, whereas that by palmitic acid was possibly associated with the PKCdependent pathway. In conclusion, the increased levels of fatty acids may be one of the reasons leading to the elevated function and expression of CYP3A4 under diabetic conditions.

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“…Data shown are the means ± SEM, * P < 0.05, significantly different as indicated revealed clear shifts in the response to extra-hepatic tumours in both the non-inflammatory and inflammatory stages (Figure 3a-c). The relationship between intrinsic metabolomics and CYP450s has been reported in several chronic metabolic diseases (Oh et al, 2012) and liver diseases (Zhang, Ramzan, & Murray, 2007). However, whether intrinsic metabolomics underlie the decreased CYP3A in the context of extra-hepatic tumours, remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Disrupted hepatic pentose phosphate pathway directly participates in and indirectly promotes CYP3A reduction: A new strategy for CYP3A‐mediated drug hepatotoxicity

Liu

Jin

Zhou

et al. 2020

British J Pharmacology

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Background and Purpose Hepatic CYP450s play an important role in drug‐induced hepatotoxicity. They are altered in liver diseases and in many non‐liver diseases, such as extra‐hepatic tumours. Consequently, CYP450‐mediated abnormal drug exposure increases the incidence and extent of hepatotoxicity. This risk is often underestimated because the mechanisms underlying decreases in hepatic CYP450s in extra‐hepatic tumours remain unclear. Experimental Approach We used Balb/c nude mice with s.c. transplanted 4T1, LoVo and HepG2 tumours to model extra‐hepatic tumours. Decreased levels of CYP3A were evaluated by qPCR, western blotting, and metabolic activity. LC‐Q/TOF‐MS and GC–MS were used in combination for analysing liver metabolomics. The contribution of the pentose phosphate pathway (PPP) to decreased CYP3A was assessed using menadione and silencing of glucose‐6‐phosphate dehydrogenase. Key Results CYP3A activity was inhibited at early stages of tumour growth when no significant inflammatory response was observed. The PPP was predominately disrupted at this non‐inflammatory stage. Disruption of the PPP directly inhibited CYP3A through the chk2/p53/p65 pathway at the non‐inflammatory stage, but at the later inflammatory stage, it indirectly potentiated the subsequent IL‐6‐mediated CYP3A decrease. Recovery of the PPP with menadione at the non‐inflammatory stage, reversed the decreased CYP3A. Similar reversal was obtained with the IL‐6 inhibitor, tocilizumab. Such modulation of the PPP to alleviate CYP3A‐mediated drug hepatotoxicity was validated with dasatinib in vivo. Conclusions and Implications PPP modulation at early, non‐inflammatory stages might provide a novel and distinctive approach to manage drug hepatotoxicity mediated by decreased CYP3A.

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Hepatic expression of cytochrome P450 in type 2 diabetic Goto–Kakizaki rats

Cited by 36 publications

References 26 publications

Next generation sequencing of sex-specific genes in the livers of obese ZSF1 rats

Next generation sequencing of sex-specific genes in the livers of obese ZSF1 rats

Increased Levels of Fatty Acids Contributed to Induction of Hepatic CYP3A4 Activity Induced by Diabetes — In Vitro Evidence From HepG2 Cell and Fa2N-4 Cell Lines

Disrupted hepatic pentose phosphate pathway directly participates in and indirectly promotes CYP3A reduction: A new strategy for CYP3A‐mediated drug hepatotoxicity

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