Differential regulation of liver P-450III cytochromes in choline-deficient rats: Implications for the erythromycin breath test as a parameter of liver function

Kolars, Joseph C.; Murray, Scott A; Peters, Ken M.; Watkins, Paul B.

doi:10.1002/hep.1840120619

Cited by 9 publications

(3 citation statements)

References 29 publications

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“…It has been reported that the amount of CYP is reduced in CD-fed and aged rats, and the degree of reduction in each CYP is regulated in a different way. [8][9][10][11] Therefore, it seems that the content of each CYP isozyme in CD-fed and aged rats might be different from that in control rats, and the contribution of CYP isozymes, except for CYP1A2, to acetanilide and caffeine metabolism could not be neglected in these rat models.…”

Section: Discussionmentioning

confidence: 99%

“…The specific activity of [8][9][10][11][12][13][14] C] caffeine was adjusted to 1924 Bq/nmol by dilution with unlabeled caffeine. Control, CDfed, aged, and MC-treated rat hepatic microsomes (0.125, 0.25, 0.0625, and 0.025 mg, respectively) were preincubated with 50 ml anti-rat CYP1A1 or CYP1A antibody for 30 min at room temperature prior to the measurement of caffeine metabolite formation.…”

Section: Quantitation Of Cyp1a2 In Hepatic Microsomesmentioning

confidence: 99%

“…[8][9][10][11] In order to examine the application of the PKCYP-test to drugs that are metabolized by multiple CYP isozymes and/or in models with reduced CYP levels, we examined the application of the PKCYP-test to the clearance of acetanilide and caffeine mediated by CYP1A2 using rats fed a choline-deficient diet and aged rats.…”

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confidence: 99%

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Application of the PKCYP-test in Cases of Altered CYP1A2 for Multiple CYP Systems in Rat Models of Disease.

Matsunaga¹,

Hattori²,

Iizasa³

et al. 2001

Biological & Pharmaceutical Bulletin

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In order to evaluate the drug metabolism capacity of individual patients, selective substrate probes have been used in vivo to identify the cytochrome P450 (CYP) isozymes involved in a variety of drug metabolism processes. 1) It has been suggested that the in vivo intrinsic clearance by hepatic metabolism can be predicted from in vitro metabolism data by the use of either liver microsomes or a recombinant system of human CYP isozymes. 2,3) Previously, we developed a novel method for determining drug metabolism capacity based on a pharmacokinetic estimation of the quantity of CYP in vivo (PKCYP-test). By using a specific probe, the drug metabolism capacity of each CYP isozyme can be estimated from the PKCYP-test incorporating the apparent liver-to-blood free concentration gradient in vivo (qg). 4) In rats whose CYP1A2 level has been induced by the administration of 3-methylcholanthrene (MCtreated rats), the amount of CYP1A2 could be predicted by the PKCYP-test using acetanilide as the probe. Furthermore, caffeine clearance could also be predicted by using the predicted amount of CYP1A2. However, there were some differences between observed and predicted values as far as the amount of CYP1A2 and caffeine clearance were concerned.Both acetanilide and caffeine have been reported to be metabolized mainly by CYP1A2 in rats. 5,6) However, there is a contradictory report that another CYP isozyme is also involved in the metabolism of caffeine. 7) Since CYP1A2 participates mainly in the metabolism of both acetanilide and caffeine in MC-treated rats, the error in predicting the amount of CYP1A2 and caffeine clearance may be negligible. It is anticipated that the role of other CYP isozymes in their metabolism might have little effect on the prediction of the amount of CYP1A2 and caffeine clearance in other models in which the CYP1A2 enzyme level is reduced. Since there are many patients with reduced CYP levels, there is a need to investigate the application of the PKCYP-test to the reduced CYP model. Moreover, it is still unclear if the PKCYP-test can be applied to drugs that are metabolized by multiple CYP isozymes.It has been reported that the amount of CYP is reduced both in rats fed a choline-deficient diet and in aged rats, and the amount of CYP in these rat models is regulated differently by each CYP isozyme. [8][9][10][11] In order to examine the application of the PKCYP-test to drugs that are metabolized by multiple CYP isozymes and/or in models with reduced CYP levels, we examined the application of the PKCYP-test to the clearance of acetanilide and caffeine mediated by CYP1A2 using rats fed a choline-deficient diet and aged rats. MATERIALS AND METHODSMaterials Chemicals were obtained from the following sources: acetanilide, p-hydroxyacetanilide, caffeine, theobromine, and theophylline were from Wako Pure Chemicals (Osaka, Japan); 3-methylcholanthrene (MC), 1,7-dimethylxanthine and 1,3,7-trimethyluric acid were from Sigma Chemical Co. (St. Louis, MO, U.S.A.); [8-14 C] caffeine was from American Radiolabeled Chemica...

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Section: Discussionmentioning

confidence: 99%

Section: Quantitation Of Cyp1a2 In Hepatic Microsomesmentioning

confidence: 99%

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Application of the PKCYP-test in Cases of Altered CYP1A2 for Multiple CYP Systems in Rat Models of Disease.

Matsunaga¹,

Hattori²,

Iizasa³

et al. 2001

Biological & Pharmaceutical Bulletin

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[13C]Aminopyrine breath test detects altered liver metabolism caused by low-dose oral contraceptives

1995

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The [13C]aminopyrine breath test measures hepatic mixed function oxidase activity. The cumulative percent dose recovered over 2 hr is a sensitive indicator of hepatic dysfunction; values < or = 7.0% have been shown to indicate severe liver disease. Previous studies have suggested that the test results may be influenced by the use of oral contraceptives steroids. We compared the results from five non-oral contraceptive-using women with those from 31 women whose duration of oral contraceptive steroid usage ranged from 4 to 204 months. The women were taking one of four oral contraceptive formulations that differed in the amounts of estrogen (20, 35, or 50 micrograms with 1 mg progesterone) and progesterone (35 micrograms estrogen with stepped levels of progesterone of 0.5, 0.75, and 1.0 mg). The [13C]aminopyrine breath test was performed on days 21 and 28 of the menstrual cycle. Cumulative percent dose recovery values among the normal menstrual cycle of non-oral contraceptive steroid-using women were 12.1 +/- 1.6 and 11.8 +/- 1.5% (mean +/- SD). In contrast, oral contraceptive steroid users showed a marked reduction in cumulative percent dose recovery at 21 days, averaging 6.1 +/- 2.3% (P < 0.001), and returned to normal values (10.2 +/- 3.5%) at 28 days in most women(seven days after oral contraceptive steroid usage was paused). The adverse impact on hepatic mixed function oxidase by oral contraceptive formulations did not differ on the basis of estrogen or progesterone content. The adverse impact of oral contraceptive usage on the mixed function oxidase activity measured by the [13C]aminopyrine breath test must be considered for women of childbearing potential.

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Cultured adult rat jejunal explants as a model for studying regulation of CYP3A

Schmiedlin-Ren

Benedict

Dobbins

et al. 1993

Biochemical Pharmacology

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Enzymes within the CYP3A subfamily are major Phase I drug-metabolizing enzymes present in hepatocytes and small bowel enterocytes. These enzymes are highly inducible in the liver by many structurally diverse compounds, including a number of commonly used medications. Studies indicate that CYP3A enzymes present in small bowel enterocytes are also inducible. However, the regulation of CYP3A enzymes in this tissue has not been well characterized, in part because in vivo studies are difficult, especially in humans. Our goals was to develop an in vitro model to study the regulation of CYP3A in enterocytes. To this end, we defined culture conditions under which adult rat jejunal explants maintained viable appearing villi for 21 hr. When dexamethasone, the prototypical inducer of CYP3A1 in rat hepatocytes, was added to the culture medium, there was a time-dependent induction of CYP3A1 mRNA and CYP3A protein in explant enterocytes which was essentially indistinguishable from the time course of induction of CYP3A1 mRNA and protein in enterocytes in vivo. This effect of dexamethasone appeared to be specific since dexamethasone had no consistent effect on the explant concentration of another enterocyte specific mRNA, intestinal fatty acid binding protein. Using this explant culture model, we found that CYP3A1 mRNA was also inducible by clotrimazole but we were unable to detect induction by rifampicin or troleandomycin. Our observations suggest that jejunal explants may provide an appropriate model for the study of the regulation of CYP3A and other drug-metabolizing enzymes.

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Differential regulation of liver P-450III cytochromes in choline-deficient rats: Implications for the erythromycin breath test as a parameter of liver function

Cited by 9 publications

References 29 publications

Application of the PKCYP-test in Cases of Altered CYP1A2 for Multiple CYP Systems in Rat Models of Disease.

Application of the PKCYP-test in Cases of Altered CYP1A2 for Multiple CYP Systems in Rat Models of Disease.

[13C]Aminopyrine breath test detects altered liver metabolism caused by low-dose oral contraceptives

Cultured adult rat jejunal explants as a model for studying regulation of CYP3A

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