Cyclosporine metabolism in human liver: Identification of a cytochrome P-450III gene family as the major cyclosporine-metabolizing enzyme explains interactions of cyclosporine with other drugs

Kronbach, Thomas; Fischer, Volker; Meyer, Urs

doi:10.1038/clpt.1988.87

Cited by 508 publications

(195 citation statements)

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“…3,4 It has been identified that the metabolism of CsA is mainly mediated by cytochrome P450 3A (CYP3A). 5 Therefore, CYP3A may importantly affect CsA pharmacokinetics.…”

Section: Introductionmentioning

confidence: 99%

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The effect of CYP3A5 polymorphism on dose-adjusted cyclosporine concentration in renal transplant recipients: a meta-analysis

et al. 2010

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Cyclosporine (CsA) is a substrate of cytochrome P450 (CYP) 3A5 and has a narrow therapeutic range with large inter-individual variability. CYP3A5*3 polymorphism is reported to be functional and may contribute to the interindividual variability. The objective of this meta-analysis was to accurately estimate the effect of CYP3A5*3 allele on CsA dose-adjusted blood concentration. A computerized literature search was conducted in PubMed. A total of 12 and 6 studies meeting the inclusion criteria were, respectively, included in meta-analysis about dose-adjusted trough concentration (C 0 /D) and dose-adjusted peak concentration (C 2 /D). The combined weighted mean difference (WMD) between CYP3A5 expressers (*1/*3 þ *1/*1) and non-expressers (*3/*3) was significant in C 2 /D (WMD ¼ À12.73 (ng ml -1 )/ (mg kg -1 ), 95% confidence interval (CI) À25.23 to À0.22, P ¼ 0.046), whereas it was marginally significant in C 0 /D (WMD ¼ À3.75 (ng ml -1 )/ (mg kg -1 ), 95% CI À7.58 to 0.07, P ¼ 0.054). Exclusion of an outlier study greatly increased the association of CYP3A5 polymorphism with C 0 /D to be significant (WMD ¼ À4.92 (ng ml -1 )/(mg kg -1 ), 95% CI: À8.27 to À1.58, P ¼ 0.011). This meta-analysis showed that CYP3A5*3 polymorphism is associated with CsA dose-adjusted concentration in renal transplant recipients. Patients carrying the CYP3A5*3/*3 genotype will require a lower dose of CsA to reach target levels compared with the CYP3A5*1/*1 or *1/*3 carriers.

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“…3,4 It has been identified that the metabolism of CsA is mainly mediated by cytochrome P450 3A (CYP3A). 5 Therefore, CYP3A may importantly affect CsA pharmacokinetics.…”

Section: Introductionmentioning

confidence: 99%

“…Of them, CYP3A4 and CYP3A5 are the major enzymes accounting for metabolism of CsA. 5 CYP3A4 is abundantly and constitutively expressed in liver and intestine. 6 According to published literature, the expression of CYP3A4 is limitedly influenced by genetic factors.…”

Section: Introductionmentioning

confidence: 99%

The effect of CYP3A5 polymorphism on dose-adjusted cyclosporine concentration in renal transplant recipients: a meta-analysis

et al. 2010

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“…leading to double-strand DNA cleavage (Tewey et al, 1984). MX2 also induces DNA double-strand breaks by the same mechanism (Horichi et al, 1990 (Kronbach et al. 1988).…”

Section: Alkaline and Neutral Elutionsmentioning

confidence: 99%

Metabolic conversion of methoxymorpholinyl doxorubicin: from a DNA strand breaker to a DNA cross-linker

Lau

Durán²,

Lewis³

et al. 1994

Br J Cancer

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“…CYP 3A4, a P450 subfamily highly expressed in human liver, is important from a pharmacological and toxicological point of view, not only because of its relative abundance in human liver (Guengerich and Turvy, 1991) but also because it is involved in the metabolism of many widely used drugs including nifedipine (Guengerich et al, 1986a), quinidine (Guengerich et al, 1986b), erythromycin and troleandomycin (Pessayre et a]., 1982;Watkins et al, 1985;Combalbert et al, 1989;Brian et al, 1990;Renaud et al, 1990), cyclosporin A (Kronbach et al, 1988;Aoyama et al, 1989;Combalbert et al, 1989), 17 a-ethynylestradiol (Guengerich, 1988), midazolam (Kronbach et al, 1989), lidocaine (Bar- (1982,1983). getzi et al.…”

mentioning

confidence: 99%

High affinity of ergopeptides for cytochromes P450 3A

Peyronneau

Delaforge

Riviere³

et al. 1994

European Journal of Biochemistry

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The interaction between rat and human liver cytochromes P450 with a series of lysergic acid derivatives and ergopeptide alkaloids was studied by difference visible spectroscopy. Ergopeptides, like bromocriptine, ergocryptine and dihydroergotamine, strongly interacted with rat liver microsomes with the appearance of a difference spectrum which is characteristic of their binding to a protein site close to the heme. The intensity of this spectrum was clearly dependent on the amounts of P450s 3A in the microsomes and was at its maximum in dexamethasone-treated rat microsomes. All the ergopeptides studied exhibited a high affinity for rat P450s 3A (K-around 1 pM), although lysergic acid derivatives not bearing the tripeptide moiety failed to give significant interactions with these P450s. A cyclic azatripeptide exhibiting a structure very similar to that of the tripeptide moiety of ergopeptides also interacted with P450s 3A with appearance of an intense type I difference spectrum. Very similar results were observed with two allelic forms of human liver P450 3A4, P450 NF25 and P450 hPCN1, produced in yeast. In both cases all the ergopeptides studied showed high affinities for the P450s (K? 0.6-2.2 pM) and an intense shift from the low-spin to the high-spin state upon substrate binding (60-100% spin shift). Lysergic acid derivatives not bearing the tripeptide group of ergopeptides also completely failed to interact with P450s 3A4.Liver microsomes from rats pretreated with dexamethasone, a specific inducer of P450 3A, were found to be particularly active for the hydroxylation of bromocriptine, which occurs at the level of its tripeptide moiety. Human liver microsomes as well as P450 NF25 and P450 hPCNl also exhibited a high activity for bromocriptine hydroxylation at this level.These results show that ergopeptides exhibit a particularly high affinity for P450s of the 3A subfamily. The tripeptide moiety of ergopeptides is essential for their recognition by P450s 3A and binds at a site close to P450 heme, producing type-I difference spectra. Accordingly, at least one of the studied ergopeptides, bromocriptine, is hydroxylated by P450s 3A at the proline ring of the cyclopeptide moiety. As cyclosporine is known to be a good substrate of P450s 3A, these results suggest that P450s 3A may be especially prone in a general manner to recognize and oxidize peptides or pseudopeptides.Cytochrome P450 enzymes constitute a superfamily of heme-thiolate proteins that catalyse the primary oxidation of a wide variety of natural endogenous substrates like steroids, fatty acids, prostaglandins, leukotrienes and lipid hydroperoxides. They also play an important role in the metabolism of exogenous compounds like drugs, procarcinogens, solvents, anesthetics and environmental pollutants. Their broad substrate specificity is now well understood on the basis of enzyme multiplicity (Gonzalez, 1992). More than 220 P450s have been sequenced and characterized; they have been classified on the basis of primary amino acid sequence similarity (Nelson et...

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Cyclosporine metabolism in human liver: Identification of a cytochrome P-450III gene family as the major cyclosporine-metabolizing enzyme explains interactions of cyclosporine with other drugs

Cited by 508 publications

References 0 publications

The effect of CYP3A5 polymorphism on dose-adjusted cyclosporine concentration in renal transplant recipients: a meta-analysis

The effect of CYP3A5 polymorphism on dose-adjusted cyclosporine concentration in renal transplant recipients: a meta-analysis

Metabolic conversion of methoxymorpholinyl doxorubicin: from a DNA strand breaker to a DNA cross-linker

High affinity of ergopeptides for cytochromes P450 3A

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