Isolation, Structural Determination, and Biological Activity of 6.alpha.-Hydroxytaxol, the Principal Human Metabolite of Taxol

Harris, James W.; Katki, Aspandiar G.; Anderson, Lawrence W.; Chmurny, Gwendolyn N.; Paukstelis, Joseph V.; Collins, Jerry M.

doi:10.1021/jm00031a022

Cited by 79 publications

(39 citation statements)

References 4 publications

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“…Moreover, our data indicate that human CYP2C8 was the only P450 involved in the formation of 6␣-OHP. These inhibition studies indicated that the minor paclitaxel metabolite in human microsomes (44% t R of paclitaxel) was apparently not the di-OHP reported by Harris et al (1994a), since it was not sufficiently inhibited by fisetin, although CYP2C8 is involved in di-OHP formation and fisetin was shown to inhibit CYP2C8.…”

Section: Variability In the Formation Of Paclitaxel Metabolitesmentioning

confidence: 93%

“…The formation of di-OHP results from stepwise catalysis by CYP2C8 and CYP3A4 (Harris et al, 1994b). 6␣-OHP was about 30-fold less active than paclitaxel in tumor cell lines in vitro (Harris et al, 1994a), and C3Ј-OHP, C2-OHP, and baccatin III were also less cytotoxic (Monsarrat et al, 1990). Human CYP1A2, 2E1, 3A4, and 3A5 expressed in Escherichia coli, HepG2, or human lymphoblastoid cells catalyzed only C3Ј-OHP formation (Harris et al, 1994b).…”

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confidence: 99%

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Different in Vitro Metabolism of Paclitaxel and Docetaxel in Humans, Rats, Pigs, and Minipigs

Václavíková

Souček²,

Svobodová³

et al. 2004

Drug Metab Dispos

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ABSTRACT:We investigated cytochrome P450 (P450)-catalyzed metabolism of the important cancer drugs paclitaxel and docetaxel in rat, pig, minipig, and human liver microsomes and cDNA-expressed P450 enzymes. In rat microsomes, paclitaxel was metabolized mainly to C3-hydroxypaclitaxel (C3-OHP) and to a lesser extent to C2-hydroxypaclitaxel (C2-OHP), di-hydroxypaclitaxel (di-OHP), and another unknown monohydroxylated paclitaxel. In pig and minipig microsomes, this unknown hydroxypaclitaxel was the main metabolite, whereas C3-OHP was a minor product. In minipigs, C2-OHP was the next minor product. In human liver microsomes, 6␣-hydroxypaclitaxel (6␣-OHP) was the main metabolite, followed by C3-OHP and C2-OHP. Among different cDNAexpressed human P450 enzymes (CYP1A2, 1B1, 2A6, 2C9, 2E1, and 3A4), only CYP3A4 enzyme formed C3-OHP and C2-OHP. Docetaxel was metabolized in pig, minipig, rat, and human liver microsomes mainly to hydroxydocetaxel (OHDTX), whereas CYP3A-induced rat microsomes produced primarily diastereomeric hydroxyoxazolidinones. Human liver microsomes from 10 different individuals formed OHDTX at different rates correlated with CYP3A4 content. Troleandomycin as a selective inhibitor of CYP3A inhibited the formation of C3-OHP, C2-OHP, and di-OHP, as well as the unknown OHP produced in rat, minipig, and pig microsomes. In human liver microsomes, troleandomycin inhibited C3-OHP and C2-OHP formation, and a suitable inhibitor of human CYP2C8, fisetin, strongly inhibited the formation of 6␣-OHP, known to be catalyzed by human CYP2C8. In conclusion, the metabolism of docetaxel is the same in all four species, but metabolism of paclitaxel is different, and 6␣-OHP remains a uniquely human metabolite. Pigs and minipigs compared with each other formed the same metabolites of paclitaxel.

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Section: Variability In the Formation Of Paclitaxel Metabolitesmentioning

confidence: 93%

mentioning

confidence: 99%

Different in Vitro Metabolism of Paclitaxel and Docetaxel in Humans, Rats, Pigs, and Minipigs

Václavíková

Souček²,

Svobodová³

et al. 2004

Drug Metab Dispos

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“…As the formation of 6a-hydroxypaclitaxel, approximately 30 times less toxic than the parent compound (Harris et al, 1994), has been shown to be the primary metabolic pathway of paclitaxel metabolism (Taniguchi et al, 2005), it would be reasonable to hypothesize that CYP2C8 polymorphisms could influence the efficacy of paclitaxel treatment. This question has been dealt with by Nakajima et al (2005), who found a 16-fold interindividual variation in the 6a-hydroxypaclitaxel area under the curve (AUC) among 23 female ovarian cancer patients, but apparently no CYP2C8 variant alleles, due to the small study or low frequency of the alleles in Japanese.…”

Section: Cyp2csmentioning

confidence: 99%

Cytochrome P450 pharmacogenetics and cancer

2006

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The cytochromes P450 (CYPs) are key enzymes in cancer formation and cancer treatment. They mediate the metabolic activation of numerous precarcinogens and participate in the inactivation and activation of anticancer drugs. Since all CYPs that metabolize xenobiotics are polymorphic, much emphasis has been put on the investigation of a relationship between the distribution of specific variant CYP alleles and risk for different types of cancer, but a consistent view does not yet exist. This is to a great extent explained by the fact that the CYPs involved in activation of precarcinogens are in general not functionally polymorphic. This is in contrast to CYPs that are active in drug biotransformation where large interindividual differences in the capacity to metabolize therapeutic drugs are seen as a consequence of polymorphic alleles with altered function. This includes also some anticancer drugs like tamoxifen and cyclophosphamide metabolized by CYP2D6, CYP2C19 and CYP2B6. Some P450 forms are also selectively expressed in tumours, and this could provide a mechanism for drug resistance, but also future therapies using these enzymes as drug targets can be envisioned. This review gives an upto-date description of our current knowledge in these areas.

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“…Taxol is known to be metabolised (Harris et al, 1994b) in the liver and inactivated (Harris et al, 1994a) by cytochrome P450 3A4. Cyclosporin A is also metabolised by cytochrome P450 3A in the liver (Villeneuve et al, 2000) and has been found to block the function of MDR (Twentyman et al, 1987).…”

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confidence: 99%

Reversal of Taxol resistance in hepatoma by cyclosporin A: involvement of the PI-3 kinase-AKT 1 pathway

Lin¹,

et al. 2003

Br J Cancer

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Hepatoma cells are known to be highly resistant to chemotherapy. Previously, we have found differential Taxol resistance in human and murine hepatoma cells. The aim of this study was to examine the effect of a multidrug resistance inhibitor, cyclosporin A in combination with Taxol on hepatoma in vitro and in vivo, and to identify the possible mechanism involved in Taxol resistance. Simultaneous treatment of cyclosporin A (0 -10 mM) and Taxol (0.1 mM) inhibited cell growth in vitro. Cyclosporin A interfered with Taxol (0.1 mM)-induced AKT activation and BAD phosphorylation. Cyclosporin A combined with Taxol treatment augments caspase-9, -3 activation and loss of mitochondrial membrane potential in HepG2 cells. PI3 kinase inhibitor, wortmannin, or a dominantnegative AKT1 expression vector treatment partially enhanced Taxol-induced apoptosis indicating that PI3 kinase-AKT pathway was involved in Taxol-resistance pathway. Moreover, combination treatment reduced tumour growth in SCID and C57BL/6 mice as compared to either Taxol or cyclosporin A treatment. Our results indicate that the combination of cyclosporin A and Taxol is effective in the reversal of Taxol resistance through the inhibition of PI3 kinase-AKT1 pathway.

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Isolation, Structural Determination, and Biological Activity of 6.alpha.-Hydroxytaxol, the Principal Human Metabolite of Taxol

Cited by 79 publications

References 4 publications

Different in Vitro Metabolism of Paclitaxel and Docetaxel in Humans, Rats, Pigs, and Minipigs

Different in Vitro Metabolism of Paclitaxel and Docetaxel in Humans, Rats, Pigs, and Minipigs

Cytochrome P450 pharmacogenetics and cancer

Reversal of Taxol resistance in hepatoma by cyclosporin A: involvement of the PI-3 kinase-AKT 1 pathway

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