Heterogeneous distribution of the cytochrome P-450 monooxygenase system in rat liver lobes.

Matsubara, Takashi; Touchi, Akira; Ogawa, Ayako

doi:10.1254/jjp.32.999

Cited by 43 publications

(15 citation statements)

References 32 publications

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“…The long-lasting effect of quinidine prolongs the biliary excretion rate of berberine, which may cause the saturation of the capacity-limited metabolism. Matsubara et al (1982) demonstrated that despite uniform protein concentration throughout rat liver, P450 monooxygenase activity was higher in homogenates prepared from the median and the right lobe relative to homogenate from the left lobe. Among these three lobes of the liver, the median lobe is the largest, with the thickest part in the center and positioned above the other two.…”

Section: Tsai and Tsaimentioning

confidence: 93%

Hepatobiliary Excretion of Berberine

Tsai¹,

Tsai²

2004

Drug Metab Dispos

143

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Berberine is a bioactive herbal ingredient isolated from the roots and bark of Berberis aristata or Coptis chinensis. To investigate the detailed pharmacokinetics of berberine and its mechanisms of hepatobiliary excretion, an in vivo microdialysis coupled with highperformance liquid chromatography was performed. In the control group, rats received berberine alone; in the drug-treated group, 10 min before berberine administration, the rats were injected with cyclosporin A (CsA), a P-glycoprotein (P-gp) inhibitor; quinidine, both organic cation transport (OCT) and P-gp inhibitors; SKF-525A (proadifen), a cytochrome P450 inhibitor; and probenecid to inhibit the glucuronidation. The results indicate that berberine displays a linear pharmacokinetic phenomenon in the dosage range from 10 to 20 mg kg ؊1, since a proportional increase in the area under the concentration-time curve (AUC) of berberine was observed in this dosage range. Moreover, berberine was processed through hepatobiliary excretion against a concentration gradient based on the bile-to-blood distribution ratio (AUC bile /AUC blood ); the active berberine efflux might be affected by P-gp and OCT since coadministration of berberine and CsA or quinidine at the same dosage of 10 mg kg ؊1 significantly decreased the berberine amount in bile. In addition, berberine was metabolized in the liver with phase I demethylation and phase II glucuronidation, as identified by liquid chromatography/tandem mass spectrometry. Also, the phase I metabolism of berberine was partially reduced by SKF-525A treatment, but the phase II glucuronidation of berberine was not obviously affected by probenecid under the present study design.

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Section: Tsai and Tsaimentioning

confidence: 93%

Hepatobiliary Excretion of Berberine

Tsai¹,

Tsai²

2004

Drug Metab Dispos

143

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“…UDP-glucuronyltransferase activity was determined in the presence of 0.03% Triton X-100 using 7-hydroxycoumarin as a substrate (13). Cytochrome P-450 in liver homogenate was detected spectropho tometrically as reported previously (14), and its content was calculated from the spectrum using the molar extinction difference of 104 mM-1 cm-1 for the absorption difference be tween the peak position (at about 450 nm) and 490 nm (15 …”

Section: Methodsmentioning

confidence: 99%

Species and sex differences in the inhibitory action of the corticosteroid alclometasone dipropionate on the hepatic drug-metabolizing system.

et al. 1989

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Abstract-The effect of successive administration of the corticosteroid alclome tasone dipropionate (ACM) on the hepatic drug-metabolizing system was ex amined using male and female rats. Although some pharmacological changes such as increases in plasma enzyme activity, lipid level and protein concentration ap peared similarly in ACM-treated male and female rats, the activities of 7-alkoxy coumarin 0-dealkylase, especially the 0-depropylation activity, decreased dose dependently by ACM administration only in male rats. ACM did not affect the hepatic drug-metabolizing activity in female rats and mice of both sexes. Also, ACM did not inhibit androgen-independent aniline hydroxylase activity even in male rats. The time course of changes of the drug-metabolizing system in male rats showed a rapid decrease in cytochrome P-450 content and 0-depropylation activity following successive treatments with ACM, but there was a slow onset in the decreases of the 0-demethylation and 0-deethylation activities of 7-alkoxy coumarin. When ACM was withdrawn, the 0-demethylation and 0-deethylation activities rapidly returned to their control levels, while recovery of the 0-depropyl ation activity was slow. These results suggested that ACM inhibits the hepatic drug-metabolizing enzyme activity associated with a specific form(s) of androgen dependent cytochrome P-450 in male rats.

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“…In a previous paper, we reported that CYP activities assessed by measurement of 7-alkoxycoumarin Odealkylase activities, which reflect various CYP isoforms 6 , showed apparent heterogeneity among the liver lobes of rats, that is, the activities in the median and right lobes were higher than those in the left lobe 7 . We also demonstrated that the susceptibility to CCl 4 -induced hepatotoxicities (CCl 4 hepatotoxicities) differed significantly among the various lobes of the rat liver, and that these differences were closely correlated with the heterogeneity of hepatic CYP activities in the different liver lobes 8 .…”

Section: Introductionmentioning

confidence: 93%

“…However, there were no other reports in the literature on investigation of the correlations between the susceptibility to CCl 4 hepatotoxicities and the hepatic CYP activities in the different liver lobes. Previously, we also reported alterations of hepatic enzyme distribution among the rat liver lobes following pretreatment with hepatic enzyme-inducing agents, phenobarbital (PB) or β-naphthoflavone (BNF) 7 . In the present study, we therefore compared the susceptibility to CCl 4 hepatotoxicities of the different liver lobes of rats enhanced by pretreatment with PB or BNF.…”

Section: Introductionmentioning

confidence: 99%

Heterogeneous Liver Lobe Responses of Carbon Tetrachloride-Induced Hepatotoxicity in Male Rats Pretreated with Hepatic Enzyme-Inducing Agents

et al. 2004

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The present study was designed to compare the susceptibility to carbon tetrachloride (CCl 4 )-induced hepatotoxicities of the different liver lobes of rats which had been subjected to pretreatment with phenobarbital sodium (PB) or β-naphthoflavone (BNF). A detailed investigation was done to determine whether the susceptibility to CCl 4 hepatotoxicities was correlated with hepatic cytochrome P450 (CYP) activities in the different liver lobes. Male Wistar rats were given a single oral administration of CCl 4 (0.1 mL/kg, dissolved in liquid paraffin) or vehicle alone following three daily intraperitoneal injections of PB (40 mg/kg, dissolved in sterile saline) or BNF (40 mg/kg, suspended in sesame oil). One day after the CCl 4 administration, all animals were necropsied, and liver samples were obtained from the left and median lobes. Each sample was used for histopathological examination and 7-alkoxycoumarin O-dealkylase activity assay to evaluate the CYP activity. All the CCl 4 -treated animals revealed typical liver damage, such as the presence of ballooning degeneration and necrosis in centrilobular hepatocytes. PB pretreatment remarkably enhanced the extent of the liver damage, which was greater in the median lobe than the left lobe. BNF pretreatment only slightly enhanced the extent of the liver damage, which was also greater in the median lobe. These results indicate the different susceptibilities of rat liver lobes to CCl 4 -induced hepatotoxicities enhanced by pretreatment with PB or BNF. Moreover, the heterogeneity of the CYP activities enhanced by PB pretreatment was closely correlated with the susceptibility to CCl 4 -induced hepatotoxicities in the different liver lobes, although that by BNF pretreatment was not. (J Toxicol Pathol 2004; 17: 223-230)

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Heterogeneous distribution of the cytochrome P-450 monooxygenase system in rat liver lobes.

Cited by 43 publications

References 32 publications

Hepatobiliary Excretion of Berberine

Hepatobiliary Excretion of Berberine

Species and sex differences in the inhibitory action of the corticosteroid alclometasone dipropionate on the hepatic drug-metabolizing system.

Heterogeneous Liver Lobe Responses of Carbon Tetrachloride-Induced Hepatotoxicity in Male Rats Pretreated with Hepatic Enzyme-Inducing Agents

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