In vitro hepatic drug metabolism and microsomal enzyme induction in genetically obese rats

Litterst, Charles L.

doi:10.1016/0006-2952(80)90502-x

Cited by 20 publications

(5 citation statements)

References 24 publications

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“…The activity of the microsomal NADPH-dependent cytochrome P-450 reductase system is probably a major source of these free radicals (Paine, 1978). Paradoxically, most reports indicate that cytochrome P-450 reductase activity and, indeed drug metabolism, is lowered in the tissues of obese animals (Litterst, 1980). The decreased cytochrome P-450-associated enzyme activity in obese mice has been attributed to genetic defects, the evidence for which centres upon the lack of inducibility of various cytochrome P-450 species (Koch et al, 1982).…”

Section: Discussionmentioning

confidence: 99%

“…Peroxidation of the plasma membranes inactivates (Na + + K + )-transporting ATPase pump activity (Trush et al, 1982), and it is possible that such decreases in Na+-K+-pump activity, which have been demonstrated (De Luise et al, 1980) in human obesity, are a consequence of increased peroxide generation. Other hepatopathological symptoms, such as impairment of drug metabolism (Litterst, 1980) and cirrhosis (Mann, 1974b;Vaughan et al, 1980), which have been associated with morbid obesity, could also be mediated through increased lipoperoxide generation, especially with the decreased activity of the primary defence enzyme, GSHPx. Further investi-gations are necessary to discover whether this defect in hepatic Se-GSHPx in these congenitally obese mice is genotypically determined or arises from their abnormal lipid metabolism in the manner discussed.…”

Section: Nadphmentioning

confidence: 99%

“…There is an intimate association between the NADPH-dependent cytochrome P-450 mono-oxygenase system and the structural phospholipid components of the ER (Lu et al, 1970). There have been a number of reports (Rouer & Leroux, 1980;Litterst, 1980) of quantitative differences (usually decreases) in drug metabolism in hepatic microsomal preparations derived from obese animals. It has also been demonstrated in congenitally obese rats that some species of cytochrome P-450 are not induced by the agents with which they are normally characterized (Koch et al, 1982).…”

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confidence: 99%

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Abnormal antioxidant defence in some tissues of congenitally obese mice

Capel¹,

Dorrell²

1984

Biochemical Journal

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The concentration of lipoperoxides (estimated as thiobarbituric acid-reactive material) and some components of the antioxidant defence system have been compared in various tissues of lean and congenitally obese mice. NADPH-stimulated lipoperoxide generation in vitro was significantly higher in microsomes (microsomal fractions) prepared from obese hepatic tissue than lean. Plasma, liver and brain lipoperoxide concentration was significantly higher in obese mice. In blood derived from obese mice the concentration of non-enzymic antioxidants including caeruloplasmin and vitamin A was higher, but hepatic retinol concentration was lower in these animals. In all the tissues assayed the glutathione peroxidase activity against H2O2 was less than its activity against cumene hydroperoxide. Assayed with either substrate, glutathione peroxidase activity was significantly higher in the brain and blood of obese mice than their lean counterparts. Conversely, liver glutathione peroxidase was decreased in obese animals, representing 43% of the activity of the lean-mouse liver enzyme against H2O2 and 81% of the cumene hydroperoxide-reducing activity. The liver of obese mice had significantly less, and the kidneys more, oxidized glutathione than the corresponding tissues of lean mice. Further investigations on hepatic tissue indicated that glutathione reductase activity was lower in the obese animals, but there was no significant difference between glucose-6-phosphate dehydrogenase activity in obese and lean mice.

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Section: Discussionmentioning

confidence: 99%

Section: Nadphmentioning

confidence: 99%

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confidence: 99%

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Abnormal antioxidant defence in some tissues of congenitally obese mice

Capel¹,

Dorrell²

1984

Biochemical Journal

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“…Phenobarbital PK were found to be different between obese Zucker and lean Zucker or SD rats (Brouwer et al, 1984), whereas altered expression and/or activity of hepatic drug metabolism enzymes cytochrome P450 2E1, CYP4A2, glutathione-S-transferase(s), and UDP-glucuronosyltransferases (UGT) were demonstrated in obese Zucker rats compared with their lean littermates (Litterst, 1980;Chaudhary et al, 1993;Enriquez et al, 1999). Recent work has shown that hepatic mRNA expression levels of Phase I and Phase II enzymes, including CYP3A1, CYP2C11, UGT1A1, UGT1A6, UGT2B1, GSTA2, and quinone reductase, as well as xenobiotic transporters Mrp2, Mrp3, and Oatp2, were downregulated in obese Zucker compared with SD rats (Kim et al, 2004).…”

Section: Introductionmentioning

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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“…Elevated levels of lipids and nr-acid glycoprotein (8) 7. Increase in hepatic size (9,10) 8. Impairment of biliary excretion due to the existence of biliary tract diseases (11) 9.…”

Section: Introductionmentioning

confidence: 99%

Influence of obesity on sulfonamide disposition in Zucker rats

Kaul

Ritschel

1988

Eur. J. Drug Metab. Pharmacokinet.

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The genetically obese Zucker rat was used as a model of obesity and compared to its lean littermate to assess and quantify obesity-altered changes in the in vivo disposition of six sulfonamides. Body composition determination indicated that the obese rats were twice the weight of lean rats and a distinct trend towards an increase in fat free mass and total body water was observed. The sulfonamide blood concentration was measured by colorimetry after a 7 mg/kg intravenous dose. All sulfonamides exhibited a biexponential decline of blood concentration with time. The volume of distribution and clearance of sulfanilamide in lean and obese rats were similar resulting in similar elimination half-lives. A decrease in clearance coupled with a trend towards an increase in volume of distribution prolonged the elimination half-life of sulfadiazine in obese rats. For sulfapyridine, sulfamerazine, sulfisomidine and sulfisoxazole, increases in the volumes of distribution and clearances resulted in similar elimination half-lives in lean and obese rats. The free fractions of the sulfonamides were significantly increased in the serum of obese rats, the influence of which on the volume of distribution and clearance is discussed.

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In vitro hepatic drug metabolism and microsomal enzyme induction in genetically obese rats

Cited by 20 publications

References 24 publications

Abnormal antioxidant defence in some tissues of congenitally obese mice

Abnormal antioxidant defence in some tissues of congenitally obese mice

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

Influence of obesity on sulfonamide disposition in Zucker rats

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