Insulin-mediated modulation of cytochrome P450 gene induction profiles in primary rat hepatocyte cultures

Sidhu, Jaspreet S.; Omiecinski, Curtis J.

doi:10.1002/(sici)1099-0461(1999)13:1<1::aid-jbt1>3.0.co;2-2

Cited by 36 publications

(27 citation statements)

References 36 publications

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“…Hepatic levels of CYP2B and CYP3A were increased in diabetic mice and rats and insulin treatment decreased them to normal levels (Sakuma et al, 2001;Yamazoe et al, 1989). In support of these observations, insulin blocks PB induction of CYP2B in rat primary hepatocytes (Yoshida et al, 1996;Sidhu and Omiecinski, 1999). In addition, we demonstrated that insulin repression of the Cyp2b10 gene is mediated by FoxO1 (Kodama et al, 2004), which co-activates CAR and augments CAR-mediated PBREM activity in HepG2 cells.…”

supporting

confidence: 79%

Phenobarbital Confers its Diverse Effects by Activating the Orphan Nuclear Receptor Car

Kodama

Negishi

2006

Drug Metabolism Reviews

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In the early 1960s, phenobarbital (PB) was shown to induce hepatic drug metabolism and the induction was implicated in the molecular mechanism of drug tolerance development. Since then, it has become evident that PB not only induces drug metabolism, but also triggers pleiotropic effects on liver function, such as cell growth and communication, proliferation of the endoplasmic reticulum, tumor promotion, glucose metabolism, steroid/ thyroid hormone metabolism, and bile acid synthesis. Upon activation by PB and numerous PB-type inducers, the nuclear receptor CAR mediates those pleiotropic actions by regulating various hepatic genes, utilizing multiple regulatory mechanisms.

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confidence: 79%

Phenobarbital Confers its Diverse Effects by Activating the Orphan Nuclear Receptor Car

Kodama

Negishi

2006

Drug Metabolism Reviews

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“…They also found a lower induction of cytochrome P450 3A1, due to phenobarbitol exposure, in cells exposed to physiological (i.e. 1 nM) concentrations of insulin (Sidhu and Omiecinski, 1999). Lemley et al (2008) found a dosedependent decrease in the relative abundance of both CYP2C and CYP3A mRNA with increasing insulin dosage in dairy cows that were challenged with a hyperinsulinemiceuglycemic clamp.…”

Section: Discussionmentioning

confidence: 93%

“…Saad et al (1994) found a dose-dependent decrease in testosterone hydroxylation at the 6b position when rat hepatocytes were cultured with increasing concentrations of insulin (1, 10 and 100 nM), a reaction that is catalyzed primarily by the cytochrome P450 3A sub-family with minimal contribution from cytochrome P450 2C13 (Ryan and Levin, 1990). Woodcroft and Novak (1999) showed that pyridine-mediated induction of cytochrome P450 2E1 mRNA and protein abundance could be substantially decreased when cells were cultured in the presence of 1 mM insulin for 96 h. Sidhu and Omiecinski (1999) found a decreased expression of cytochrome P450 3A1 in rat hepatocytes cultured with 1 mM insulin and then exposed to phenobarbitol, a known cytochrome P450 3A1 inducer. They also found a lower induction of cytochrome P450 3A1, due to phenobarbitol exposure, in cells exposed to physiological (i.e.…”

Section: Discussionmentioning

confidence: 99%

Concomitant changes in progesterone catabolic enzymes, cytochrome P450 2C and 3A, with plasma insulin concentrations in ewes supplemented with sodium acetate or sodium propionate

Lemley

Koch

Blemings

et al. 2008

Animal

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Progesterone is essential for maintaining pregnancy, and several authors have suggested that low peripheral concentrations of progesterone may be responsible for high rates of embryonic loss. The primary organ involved in the catabolism of progesterone is the liver, and cytochrome P450 2C and 3A sub-families account for a large proportion of this catabolism. Elucidating a mechanism to decrease progesterone catabolism, thereby increasing embryonic and uterine exposure to progesterone, seems a logical approach to ameliorate high rates of embryonic loss. The objectives of the current experiment were to determine the pattern of insulin secretion after supplementing feed with either sodium acetate or sodium propionate and to determine any association between the differential patterns of insulin secretion with the hepatic activity of cytochrome P450 2C and 3A and progesterone clearance. Sixteen ovariectomized ewes were fed 3 kg/day for 10 days of a diet consisting of 50% corn silage, 38% triticale haylage, 12% soybean meal and 600 ml of 3.5 M sodium acetate (energy control; n 5 8) or 2.0 M sodium propionate (gluconeogenic substrate; n 5 8). Equal portions of the ration (1 kg as-fed basis along with 200 ml of 3.5 M sodium acetate or 2.0 M sodium propionate) were offered three times daily at 0600, 1400 and 2200 h. Concentrations of insulin in plasma were determined immediately before feeding and at 15, 30, 60, 90, 120, 180, 240 and 300 min after feeding. Progesterone clearance from peripheral circulation (ng/ml per min) was measured by giving a 5 mg injection of progesterone into the left jugular vein and collecting blood via the right jugular vein at 0, 2, 4, 6, 8, 10, 15, 20 and 30 min afterwards. Liver biopsies were taken 1 h after feeding to determine cytochrome P450 2C and 3A activities. Insulin concentrations in ewes supplemented with sodium propionate were elevated at 15, 30 and 60 min after feeding compared to the sodium acetate group. Cytochrome P450 2C and 3A activities were decreased 1 h after feeding in the sodium propionate-treated ewes relative to sodium acetate. Insulin appears to down-regulate cytochrome P450 activity, which could be used to decrease the catabolism of progesterone during early gestation, thereby increasing peripheral concentrations of progesterone and, consequently, embryonic exposure to progesterone.

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“…Although insulin repression of PB induction was reported for rat primary hepatocytes (17,42), it has not been demonstrated in mouse primary hepatocytes. Upon finding that FOXO1 is a key coactivator of CAR in HepG2 cells, we examined whether insulin repressed the induction of the Cyp2b10 gene by TCPOBOP in mouse primary hepatocytes (Fig.…”

Section: Figmentioning

confidence: 89%

“…In contrast, insulin is known to repress the induction of drug-metabolizing activity by certain drugs and in diabetic livers (44,49,56). Insulin treatment either eliminated or significantly reduced PB induction of CYP2B in rat primary hepatocytes (17,42,58). Hepatic CYP2B, CYP3A, and CYP4A were increased in experimentally generated diabetic rats and mice and were reduced to normal levels by insulin treatment (37, 56).…”

mentioning

confidence: 99%

Nuclear Receptors CAR and PXR Cross Talk with FOXO1 To Regulate Genes That Encode Drug-Metabolizing and Gluconeogenic Enzymes

Kodama

Koike

Negishi

et al. 2004

Molecular and Cellular Biology

302

269

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The nuclear receptors CAR and PXR activate hepatic genes in response to therapeutic drugs and xenobiotics, leading to the induction of drug-metabolizing enzymes, such as cytochrome P450. Insulin inhibits the ability of FOXO1 to express genes encoding gluconeogenic enzymes. Induction by drugs is known to be decreased by insulin, whereas gluconeogenic activity is often repressed by treatment with certain drugs, such as phenobarbital (PB). Performing cell-based transfection assays with drug-responsive and insulin-responsive enhancers, glutathione S-transferase pull down, RNA interference (RNAi), and mouse primary hepatocytes, we examined the molecular mechanism by which nuclear receptors and FOXO1 could coordinately regulate both enzyme pathways. FOXO1 was found to be a coactivator to CAR-and PXR-mediated transcription. In contrast, CAR and PXR, acting as corepressors, downregulated FOXO1-mediated transcription in the presence of their activators, such as 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) and pregnenolone 16␣-carbonitrile, respectively. A constitutively active mutant of the insulin-responsive protein kinase Akt, but not the kinase-negative mutant, effectively blocked FOXO1 activity in cell-based assays. Thus, insulin could repress the receptors by activating the Akt-FOXO1 signal, whereas drugs could interfere with FOXO1-mediated transcription by activating CAR and/or PXR. Treatment with TCPOBOP or PB decreased the levels of phosphoenolpyruvate carboxykinase 1 mRNA in mice but not in Car ؊/؊ mice. We conclude that FOXO1 and the nuclear receptors reciprocally coregulate their target genes, modulating both drug metabolism and gluconeogenesis.Liver plays a major role in the metabolism of therapeutic drugs and environmental contaminants. It is endowed with a mechanism to induce hepatic enzymes, leading to increased detoxification and elimination of those xenobiotics. Drug induction is generally regulated by transcriptional activation of hepatic genes encoding drug-metabolizing enzymes, such as cytochrome P450s (CYPs) and specific transferases. Acting as the principal transcription factors which also form complexes with RXR, the nuclear receptors CAR and PXR play a central role in induction by binding to the phenobarbital (PB)-and xenobiotic-responsive enhancer modules PBREM and XREM (5,6,11,12,18,46,53), respectively, and activating transcription of their target genes, such as CYP genes, in response to a distinct but overlapping group of xenobiotics (23, 36, 50). However, induction is heavily influenced by endocrine conditions; glucocorticoid hormone, for example, augments CYP induction by PB (31). In contrast, insulin is known to repress the induction of drug-metabolizing activity by certain drugs and in diabetic livers (44,49,56). Insulin treatment either eliminated or significantly reduced PB induction of CYP2B in rat primary hepatocytes (17,42,58). Hepatic CYP2B, CYP3A, and CYP4A were increased in experimentally generated diabetic rats and mice and were reduced to normal levels by insulin treatmen...

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Insulin-mediated modulation of cytochrome P450 gene induction profiles in primary rat hepatocyte cultures

Cited by 36 publications

References 36 publications

Phenobarbital Confers its Diverse Effects by Activating the Orphan Nuclear Receptor Car

Phenobarbital Confers its Diverse Effects by Activating the Orphan Nuclear Receptor Car

Concomitant changes in progesterone catabolic enzymes, cytochrome P450 2C and 3A, with plasma insulin concentrations in ewes supplemented with sodium acetate or sodium propionate

Nuclear Receptors CAR and PXR Cross Talk with FOXO1 To Regulate Genes That Encode Drug-Metabolizing and Gluconeogenic Enzymes

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