Effect of phenobarbital on intralobular expression of CYP2B1/2 in livers of rats

Watanabe, Jun; Mondo, Hiroko; Takamori, Yasuharu; Takeda, Kazuo; Kanamura, Shinsuke

doi:10.1016/s0006-2952(00)00320-8

Cited by 7 publications

(2 citation statements)

References 26 publications

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“…In this experiment, phenobarbital was used to induce the P450 enzymes that metabolize compounds such as α-HCH in the rat. Specific enzymes were not of concern, but CYP2B1 and CYP2B2 are known to be induced by this treatment ( , ). As expected, the average α-HCH concentration of a given tissue at 24 h is statistically lower in the phenobarbital treated animals as compared to the control animals, confirming that P450 enzymes that metabolize α-HCH have been induced.…”

Section: Resultsmentioning

confidence: 99%

“…The present study develops the laboratory rat as a model for these findings in wildlife. Phenobarbital was used to induce cytochrome P450, such as CYP2B1 and CYP2B2 ( , ), enzymes that are primarily responsible for the metabolism of xenobiotics (). We also used rat tissue slices to determine if enantioselective metabolism is occurring in brain or liver tissues.…”

Section: Introductionmentioning

confidence: 99%

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Understanding Enantioselective Processes: A Laboratory Rat Model for α-Hexachlorocyclohexane Accumulation

Ulrich

Willett

Caperell-Grant

et al. 2001

Environ. Sci. Technol.

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Since cyclodextrin gas chromatography columns became popular for chiral separations, many researchers have noticed high enantiomeric ratios [ER: (+)-enantiomer/(-)-enantiomer] for alpha-HCH in the brains of wildlife. This investigation used the laboratory rat as a model for these phenomena. Rats were either pretreated with phenobarbital (PB) or left untreated and then dosed with alpha-HCH. Animals were sacrificed after 1 or 24 h. The ER averaged 0.95 +/- 0.01 in blood, 1.29 +/- 0.02 in fat, and 0.77 +/- 0.004 in liver. ERs in brain ranged from 2.8 +/- 0.5 to 13.5 +/- 0.4. Both the tissue concentration distribution and the ERs agree well with those previously reported in wildlife. To determine whether high brain ERs were due to enantioselective metabolism or transport through the blood-brain barrier, alpha-HCH exposed brain and liver tissue slices were compared. Concentrations in the brain slices did not decrease with PB pretreatment but did decrease in the liver slices. Enantiomeric ratios in the brain slices averaged 1.11 +/- 0.02 and were 0.76 +/- 0.03 in liver slices for the PB pretreated rats. These data indicate that the enantioselective metabolism of alpha-HCH by the brain is not the mechanism responsible for high ERs in this tissue.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Understanding Enantioselective Processes: A Laboratory Rat Model for α-Hexachlorocyclohexane Accumulation

Ulrich

Willett

Caperell-Grant

et al. 2001

Environ. Sci. Technol.

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Identification of rat cytochrome P450 forms involved in the metabolism of clausenamide enantiomers

Zhu¹,

Zhang²

2003

Chirality

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To identify which cytochrome P450 (CYP) isoform(s) are responsible for the metabolism of clausenamide (CLA) enantiomers in rats, effects of various CYP isoform inducers and inhibitors on the formation of CLA metabolites were investigated in liver microsomes. In incubations with rat liver microsomes, CLA enantiomers were mainly converted to 4-hydroxy, 5-hydroxy, and 7-hydroxy-metabolites. 4-OH-CLA was the major metabolite of (+)-3R, 4S, 5S, 6R-CLA [(+)-CLA], while 7-OH-CLA was the major one of (-)-3S, 4R, 5R, 6S-CLA [(-)-CLA]. In induction studies, enzymatic parameters were used to assess the role of different CYP forms in CLA hydroxylation reactions. A marked increase in the rate of metabolism of CLA enantiomers was observed in microsomes of dexamethasone treated rats, V(max)/K(m) values for 4-OH-(+)-CLA, 7-OH-, 5-OH-, and 4-OH-(-)-CLA were 5.3, 6.5, 3.0, and 5.9 times higher than those in control microsomes, respectively. Rifampicin treatment caused corresponding 1.7-, 2.6-, 3.1-, and 2.8-fold increases. Dex and Rif also increased in the amount of (+)-5- and (+)-7-OH-CLA that were not detectable in the control group. These results suggested that inducible CYP3A1 was involved in the hydroxylation of CLA enantiomers. In inhibition studies, ketoconazone (6.25 microM) completely inhibited the production of main metabolites of (-)-CLA (100%) and (+)-CLA (97%). Triacetyloleandomycin (12.5 microM) strongly inhibited the corresponding metabolites by 34-85%. These findings also indicated that institutive CYP3A2 shared a major role in the hydroxylation of CLA enantiomers with CYP3A1 in untreated rats. Together, the data suggested that CYP3A was the predominant isoform responsible for the metabolism of CLA enantiomers.

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Effects of choline‐deprivation on paracetamol‐ or phenobarbital‐induced rat liver metabolic response

Konstandi

Segos

Galanopoulou

et al. 2008

J of Applied Toxicology

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Choline is an essential nutrient that seems to be involved in a wide variety of metabolic reactions and functions in both humans and rodents. Various pathophysiological states have been linked to choline deprivation (CD). The aim of the present study was to determine the effect of CD upon biochemical, histological and metabolic alterations induced by drugs that affect hepatic functional integrity and various drug metabolizing systems via distinct mechanisms. For this purpose, paracetamol (ACET) or phenobarbital (PB) were administered to male Wistar rats that were fed with standard rodent chow (normally fed, NF) or underwent dietary CD. The administration of ACET increased the serum aspartate aminotransferase levels in NF rats, while CD restricted this increase. On the other hand, ACET suppressed alkaline phosphatase levels only in CD rats. Moreover, CD prevented the PB-induced increase of the mitotic activity of hepatocytes. The administration of ACET down-regulated CYP1A2 and CYP2B1 expression in CD rats, while up-regulating them in NF rats. The administration of PB suppressed CYP1A2 apoprotein levels in CD rats, whereas the drug had no effect on NF rats. The PB-induced up-regulation of CYP2B, CYP2E1 and CYP1A1 isozymes was markedly higher in CD than in NF rats. In addition, PB increased glutathione-S-transferase activity only in CD rats. Hepatic glutathione content (GSH) was suppressed by ACET in NF rats, whereas the drug increased GSH in CD rats. Our data suggest that CD has a significant impact on the hepatic metabolic functions, and in particular on those related to drug metabolism. Thus, CD may modify drug effectiveness and toxicity, as well as drug-drug interactions, particularly those related to ACET and PB.

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Effect of phenobarbital on intralobular expression of CYP2B1/2 in livers of rats

Cited by 7 publications

References 26 publications

Understanding Enantioselective Processes: A Laboratory Rat Model for α-Hexachlorocyclohexane Accumulation

Understanding Enantioselective Processes: A Laboratory Rat Model for α-Hexachlorocyclohexane Accumulation

Identification of rat cytochrome P450 forms involved in the metabolism of clausenamide enantiomers

Effects of choline‐deprivation on paracetamol‐ or phenobarbital‐induced rat liver metabolic response

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