Effects of phenobarbitone and β-naphthoflavone on hepatic microsomal drug metabolising enzymes of the male beagle dog

McKillop, D

doi:10.1016/0006-2952(85)90159-5

Cited by 20 publications

(7 citation statements)

References 21 publications

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“…Several studies have shown that a select compound can cause induction of one or more P450 enzymes in dog (McKillop and Pickup, 1991;Robertson et al, 1995;Nishibe and Hirata, 1995;McKillop et al, 1998;Mae et al, 1998). However, little information is available on the profile of P450 enzymes induced by prototypical P450 enzyme inducers, namely, those that cause CYP1A, CYP2B, CYP2E, CYP3A, or CYP4A induction in other mammalian species (McKillop 1985;Nishibe and Hirata, 1993;Nishibe and Hirata, 1995;Nishibe et al, 1998). Along with enzyme induction, a large number of chemically diverse compounds have been shown to cause hepatic hyperplasia and proliferation of the endoplasmic reticulum and peroxisomes in rodents.…”

Section: Resultsmentioning

confidence: 99%

“…Although EROD activity has not been shown to be specific for dog CYP1A as it has for the rat, there is indirect evidence suggesting that dog CYP1A catalyzes EROD. McKillop (1985) reported that EROD activity increases 3-to 5-fold in dogs treated with the CYP1A inducer ␤-naphthoflavone but not with the CYP2B inducer phenobarbital. CYP1A1 and CYP1A2 mRNA are expressed at low levels in the liver of untreated dogs, but the levels increase after treatment with the polychlorinated biphenyl mixture, Kaneclor KC-500 (Uchida et al, 1990).…”

Section: Resultsmentioning

confidence: 99%

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In Vivo and in Vitro Induction of Cytochrome P450 Enzymes in Beagle Dogs

Graham

Downey²,

Mudra³

et al. 2002

Drug Metab Dispos

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ABSTRACT:The aim of this study was to determine the in vitro and in vivo effects of several prototypical inducers, namely ␤-naphthoflavone, 3-methylcholanthrene, phenobarbital, isoniazid, rifampin, and clofibric acid, on the expression of cytochrome P450 (P450) enzymes in beagle dogs. For the in vitro induction study, primary cultures of dog hepatocytes were treated with enzyme inducers for 3 days, after which microsomes were prepared and analyzed for P450 activities. For the in vivo induction study, male and female beagle dogs were treated with enzyme inducers for 4 days (with the exception of phenobarbital, which was given for 14 days), after which the livers were removed and microsomal P450 activities were determined ex vivo. Treatment of male beagle dog hepatocyte cultures (n ‫؍‬ 3) with ␤-naphthoflavone or 3-methlychloranthrene resulted in up to a 75-fold increase in microsomal 7-ethoxyresorufin O-dealkylase (CYP1A1/2) activity, whereas in vivo treatment of male and female beagle dogs with ␤-naphthoflavone followed by ex vivo analysis resulted in up to a 24-fold increase. Phenobarbital caused a 13-fold increase in 7-benzyloxyresorufin O-dealkylase (CYP2B11) activity in vitro and up to a 9.9-fold increase in vivo. Isoniazid had little or no effect on 4-nitrophenol hydroxylase activity in vitro. Rifampin caused a 13-fold induction of testosterone 6␤-hydroxylase (CYP3A12) activity in vitro and up to a 4.5-fold increase in vivo. Treatment of dogs in vivo or dog hepatocytes in vitro with clofibric acid appeared to have no effect on CYP4A activity as determined by the 12-hydroxylation of lauric acid. In general, the absolute rates (picomoles per minute per milligram of microsomal protein) of P450 reactions catalyzed by microsomes from cultured hepatocytes (i.e., in vitro rates) were considerably lower than those catalyzed by microsomes from dog liver (i.e., ex vivo rates). These results suggest that beagle dogs have CYP1A, CYP2B, CYP2E, and CYP3A enzymes and that the induction profile resembles the profile observed in humans more than in rats.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

In Vivo and in Vitro Induction of Cytochrome P450 Enzymes in Beagle Dogs

Graham

Downey²,

Mudra³

et al. 2002

Drug Metab Dispos

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“…Similarly the dog has also been reported to be less sensitive to the barbiturate than are rodents (McKillop, 1985;Muller et al, 2000) and in general both the nonhuman primate and the dog have been reported to be less responsive to the induction of enzymes by so-called classic inducers of rodent hepatic enzymes. Figure 10 gives some data from the paper by Amacher et al (2001) on the hepatic response of the dog liver to a number of rodent hepatic enzyme inducing chemicals.…”

Section: Drug-induced Nonneoplastic Hepatic Changesmentioning

confidence: 99%

Spontaneous and Drug-Induced Hepatic Pathology of the Laboratory Beagle Dog, the Cynomolgus Macaque and the Marmoset

Foster

2005

Toxicol Pathol

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This review focuses on the background hepatic pathology present in three of the most commonly used species in the safety assessment of drugs, namely the beagle dog, the marmoset and the cynomolgus macaque. Both the nonneoplastic and neoplastic pathology are reviewed with a discussion on the potential impact that significant background pathology might have on the interpretation of any drug-induced pathology during subsequent testing. Although specific instances, such as parasitological infection in wild-caught primates can pose problems of interpretation, in general the background pathology in both the dog and the nonhuman primates, is not significantly different from that seen in the liver of laboratory rodents and with experience should not pose significant problems for the experienced pathologist. The relative merits of the primate versus the dog as a choice of second species are also considered in some detail. Although there is an inbuilt prejudice that the primate will more closely mimic subsequent effects that might occur in man in the clinic, insofar as the liver is concerned, there are many instances where the dog has been more representative of human exposure and metabolism and there is little evidence to show that the nonhuman primate is consistently better than dog in predicting human liver toxicity. As with most areas of science, comparative toxicology would dictate that the more information gained, from as wide a range of species as is practical, will give the best assessment for any subsequent problems in the clinic. This pragmatic approach should prove to be more successful than one based entirely upon an assumption, and in many cases the assumption is incorrect, that the primate always predicts human toxicity better than the nonprimate, including the dog.

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“…Specific activity was calculated as nmol 7-hydroxycoumarin formed x mg DNA-1 x min-1. Aldrin epoxidase activity (Me Killop, 1985) was estimated by measuring the amount of dieldrin formed and calculated as nmol dieldrin formed x mg DNA -1 x min -1. Activity of fatty acid synthase (EC 2.3.1.85), malic enzyme (EC 1.1.1.40) and glucose-6 -phosphate dehydrogenase (EC 1.1.1.49) was estimated as previously de scribed (Boll et al,1996).…”

Section: Enzyme Assaysmentioning

confidence: 99%

“…7-Ethoxycoumarin-O-deethylase activity was measured fluorometrically (Me Killop, 1985), following the production of 7-hydroxycoumarin. A calibration curve with 7-hydroxycoumarin (5-100 ng) was used.…”

Section: Enzyme Assaysmentioning

confidence: 99%

Pathogenesis of Carbon Tetrachloride-Induced Hepatocyte Injury Bioactivation of CCl₄ by Cytochrome P450 and Effects on Lipid Homeostasis

Boll

Weber

Becker

et al. 2001

Zeitschrift Für Naturforschung C

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Liver Damage, Carbon Tetrachloride, Cytochrome P450The CCl4-induced development of liver damage was studied in monolayer cultures of pri mary rat hepatocytes:(1) CC14 caused accumulation of triglycerides in hepatocytes following cytochrome P450 induction with ß-naphthoflavone or metyrapone. Ethanol or a high dose of insulin plus triio dothyronine had the same effect. (2) CC14 increased the synthesis of fatty acids and triglycer ides and the rate of lipid esterification. Cholesterol and phospholipid synthesis from acetate was also increased. (3) CC14 reduced ß-oxidation of fatty acids as assessed by C 0 2-release and ketone body formation. Hydrolysis of triglycerides was also reduced. (4) The content of unsaturated fatty acids in microsomal lipids was decreased by almost 50% after incubation with CCI4, while saturated fatty acids increased slightly. (5) CC14 exerted a pronounced inhib itory effect on the exocytosis of macromolecules (albumin), but did not affect secretion of bile acids from hepatocytes.

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Effects of phenobarbitone and β-naphthoflavone on hepatic microsomal drug metabolising enzymes of the male beagle dog

Cited by 20 publications

References 21 publications

In Vivo and in Vitro Induction of Cytochrome P450 Enzymes in Beagle Dogs

In Vivo and in Vitro Induction of Cytochrome P450 Enzymes in Beagle Dogs

Spontaneous and Drug-Induced Hepatic Pathology of the Laboratory Beagle Dog, the Cynomolgus Macaque and the Marmoset

Pathogenesis of Carbon Tetrachloride-Induced Hepatocyte Injury Bioactivation of CCl₄ by Cytochrome P450 and Effects on Lipid Homeostasis

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Effects of phenobarbitone and β-naphthoflavone on hepatic microsomal drug metabolising enzymes of the male beagle dog

Cited by 20 publications

References 21 publications

In Vivo and in Vitro Induction of Cytochrome P450 Enzymes in Beagle Dogs

In Vivo and in Vitro Induction of Cytochrome P450 Enzymes in Beagle Dogs

Spontaneous and Drug-Induced Hepatic Pathology of the Laboratory Beagle Dog, the Cynomolgus Macaque and the Marmoset

Pathogenesis of Carbon Tetrachloride-Induced Hepatocyte Injury Bioactivation of CCl4 by Cytochrome P450 and Effects on Lipid Homeostasis

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Product

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Pathogenesis of Carbon Tetrachloride-Induced Hepatocyte Injury Bioactivation of CCl₄ by Cytochrome P450 and Effects on Lipid Homeostasis