Significantly reduced cytochrome P450 3A4 expression and activity in liver from humans with diabetes mellitus

Dostálek, Miroslav; Court, Michael H.; Yan, Bingfang; Akhlaghi, Fatemeh

doi:10.1111/j.1476-5381.2011.01270.x

Cited by 112 publications

(125 citation statements)

References 36 publications

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“…An alternate approach is to use midazolam, a selective phenotypic probe for CYP3A, which is not a substrate for uptake or efflux drug transporters (Nolin et al, 2009). In the present study, we evaluated the function of CYP3A using the well established probe substrates, midazolam and testosterone (Guengerich, 1999;Dostalek et al, 2011). Our results demonstrate that as kidney function declines, there is a rapid decrease in CYP3A-enzymatic activity.…”

Section: Discussionmentioning

confidence: 89%

Down-Regulation of Hepatic CYP3A and CYP2C Mediated Metabolism in Rats with Moderate Chronic Kidney Disease

Velenosi¹,

Fu²,

Luo³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Expression and activity of drug-metabolizing enzymes are decreased in severe kidney disease; however, only a small percentage of patients with chronic kidney disease (CKD) are at the final stage of the disease. This study aimed to determine the changes in drug-metabolizing enzyme function and expression in rats with varying degrees of kidney disease. Sprague-Dawley rats were subjected to surgical procedures that allowed the generation of three distinct models of kidney function: normal kidney function, moderate kidney function, and severe kidney disease. Forty-two days after surgery, rats were sacrificed and hepatic CYP3A and CYP2C expression was determined. In addition, enzymatic activity was determined in liver microsomes by evaluating midazolam (CYP3A), testosterone (CYP3A and CYP2C), and tolbutamide (CYP2C) enzyme kinetics. Both moderate and severe kidney disease were associated with a reduction in CYP3A2 and CYP2C11 expression (p < 0.05). Likewise, moderate kidney disease resulted in more than a 60% decrease in enzyme activity (V max ) for CYP2C11 and CYP3A, compared with controls (p < 0.05). When the degree of kidney disease was correlated with metabolic activity, an exponential decline in CYP2C-and CYP3A-mediated metabolism was observed. Our results demonstrate that CYP3A and CYP2C expression and activity are decreased in both moderate and severe CKD. Our data suggest that drug metabolism is significantly decreased in the earlier stages of CKD and imply that patients with moderate CKD may be subject to unpredictable pharmacokinetics.

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Section: Discussionmentioning

confidence: 89%

Down-Regulation of Hepatic CYP3A and CYP2C Mediated Metabolism in Rats with Moderate Chronic Kidney Disease

Velenosi¹,

Fu²,

Luo³

et al. 2012

Drug Metab Dispos

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“…A significant increase in hepatic CYP2E1 activity, assessed through chlorzoxazone disposition, was observed in obese type 2 patients with diabetes and confirmed through increased protein levels through Western blots and greater chlorzoxazone 6-hydroxylation activity in diabetic human liver microsomes (Wang et al, 2003). In contrast, a significant decrease in hepatic CYP3A4 enzymatic activity and protein level has been associated with diabetes (Dostalek et al, 2011b). Several culprits have been hypothesized for the decreased CYP3A4 expression in diabetic liver.…”

Section: Discussionmentioning

confidence: 96%

“…Several culprits have been hypothesized for the decreased CYP3A4 expression in diabetic liver. These include the effects of proinflammatory cytokines (Morgan, 1997), noncytokine components, and oxidative stress (Dostalek et al, 2011b). Expression of CYP3A4 was found to be downregulated by interleukin-1b, IL-6 (Sunman et al, 2004), interferon-g (Donato et al, 1997), and hepatocyte growth factor (Donato et al, 1998) in vitro in human hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

Difference in the Pharmacokinetics and Hepatic Metabolism of Antidiabetic Drugs in Zucker Diabetic Fatty and Sprague-Dawley Rats

Zhou¹,

Rougée²,

Bedwell³

et al. 2016

Drug Metabolism and Disposition

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The Zucker diabetic fatty (ZDF) rat, an inbred strain of obese Zucker fatty rat, develops early onset of insulin resistance and displays hyperglycemia and hyperlipidemia. The phenotypic changes resemble human type 2 diabetes associated with obesity and therefore the strain is used as a pharmacological model for type 2 diabetes. The aim of the current study was to compare the pharmacokinetics and hepatic metabolism in male ZDF and Sprague-Dawley (SD) rats of five antidiabetic drugs that are known to be cleared via various mechanisms. Among the drugs examined, metformin, cleared through renal excretion, and rosiglitazone, metabolized by hepatic cytochrome P450 2C, did not exhibit differences in the plasma clearance in ZDF and SD rats. In contrast, glibenclamide, metabolized by hepatic CYP3A, canagliflozin, metabolized mainly by UDP-glucuronosyltransferases (UGT), and troglitazone, metabolized by sulfotransferase and UGT, exhibited significantly lower plasma clearance in ZDF than in SD rats after a single intravenous administration. To elucidate the mechanisms for the difference in the drug clearance, studies were performed to characterize the activity of hepatic drug-metabolizing enzymes using liver S9 fractions from the two strains. The results revealed that the activity for CYP3A and UGT was decreased in ZDF rats using the probe substrates, and decreased unbound intrinsic clearance in vitro for glibenclamide, canagliflozin, and troglitazone was consistent with lower plasma clearance in vivo. The difference in pharmacokinetics of these two strains may complicate pharmacokinetic/ pharmacodynamic correlations, given that ZDF is used as a pharmacological model, and SD rat as the pharmacokinetics and toxicology strain.

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“…Moreover, those studies that noted decreased CYP3A4 protein expression differed with respect to whether CYP3A4 mRNA was also reduced (Niemelä et al, 2000;Fisher et al, 2009). In a study of donated human type 2 diabetic liver, where NAFLD has a prevalence of 50%, hepatic CYP3A4 expression was reduced (Dostalek et al, 2011). Taken together, a majority of studies to date suggest that NAFLD is associated with reduced hepatic CYP3A activity; however, the data are heterogeneous and this finding has not yet been demonstrated in vivo.…”

Section: Introductionmentioning

confidence: 89%

CYP3A Activity and Expression in Nonalcoholic Fatty Liver Disease

Woolsey¹,

Mansell²,

Kim³

et al. 2015

Drug Metab Dispos

109

113

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Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver disease in the Western world, given its association with obesity, type 2 diabetes, and dyslipidemia. Medications are widely used in NAFLD to manage comorbid conditions, and there is significant interest in developing new drug therapies to treat the disease. Despite this, little is known about the effects of NAFLD on drug metabolism. We examined the activity and expression of the major drug-metabolizing enzyme subfamily, CYP3A, in subjects with NAFLD as well as in mouse and cellular models. CYP3A activity was determined in healthy volunteers and subjects with biopsy-proven NAFLD by oral midazolam phenotyping and measurement of plasma 4b-hydroxycholesterol, an endogenous metabolic biomarker. CYP3A4 transcriptional activity, metabolic activity, and expression were also assessed in a mouse and cellular model of NAFLD. Subjects with nonalcoholic steatohepatitis (NASH) had 2.4-fold higher plasma midazolam levels compared with controls. Plasma 4b-hydroxycholesterol was 51% and 37% lower than controls in subjects with simple steatosis and NASH, respectively. Fibrosis was associated with 57% lower plasma 4b-hydroxycholesterol levels than controls. Furthermore, hepatic CYP3A4 mRNA expression in NASH was 69% lower than control livers. CYP3A4 gene luciferase activity in the livers of NAFLD mice was 38% lower than that of controls. Lipidloaded Huh7 human hepatoma cells had a 38% reduction in CYP3A4 activity and 80% lower CYP3A4 mRNA expression compared with the control. CYP3A activity is reduced in human NAFLD in addition to mouse and in vitro cell models of the disease.

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Significantly reduced cytochrome P450 3A4 expression and activity in liver from humans with diabetes mellitus

Cited by 112 publications

References 36 publications

Down-Regulation of Hepatic CYP3A and CYP2C Mediated Metabolism in Rats with Moderate Chronic Kidney Disease

Down-Regulation of Hepatic CYP3A and CYP2C Mediated Metabolism in Rats with Moderate Chronic Kidney Disease

Difference in the Pharmacokinetics and Hepatic Metabolism of Antidiabetic Drugs in Zucker Diabetic Fatty and Sprague-Dawley Rats

CYP3A Activity and Expression in Nonalcoholic Fatty Liver Disease

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