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Expression of paclitaxel-inactivating CYP3A activity in human colorectal cancer: implications for drug therapy.
Br J Cancer. 2002 Sep 09; 87(6):681-6.BJ

Abstract

Cytochrome P450 3A is a drug-metabolising enzyme activity due to CYP3A4 and CYP3A5 gene products, that is involved in the inactivation of anticancer drugs. This study analyses the potential of cytochrome P450 3A enzyme in human colorectal cancer to impact anticancer therapy with drugs that are cytochrome P450 3A substrates. Enzyme activity, variability and properties, and the ability to inactivate paclitaxel (taxol) were analysed in human colorectal cancer and healthy colorectal epithelium. Cytochrome P450 3A enzyme activity is present in healthy and tumoral samples, with a nearly 10-fold interindividual variability. Nifedipine oxidation activity+/-s.d. for colorectal cancer microsomes was 67.8+/-36.6 pmol min(-1) mg(-1). The K(m) of the tumoral enzyme (42+/-8 microM) is similar to that in healthy colorectal epithelium (36+/-8 microM) and the human liver enzyme. Colorectal cancer microsomes metabolised the anticancer drug paclitaxel with a mean activity was 3.1+/-1.2 pmol min(-1) mg(-1). The main metabolic pathway is carried out by cytochrome P450 3A, and it is inhibited by the cytochrome P450 3A-specific inhibitor ketoconazole with a K(I) value of 31 nM. This study demonstrates the occurrence of cytochrome P450 3A-dependent metabolism in colorectal cancer tissue. The metabolic activity confers to cancer cells the ability to inactivate cytochrome P450 3A substrates and may modulate tumour sensitivity to anticancer drugs.

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Authors+Show Affiliations

Martínez C
Department of Pharmacology, Medical School, University of Extremadura, Avda. de Elvas s/n, E-06071, Badajoz, Spain.
García-Martín E
No affiliation info available
Pizarro RM
No affiliation info available
García-Gamito FJ
No affiliation info available
Agúndez JA
No affiliation info available

MeSH

AgedAntineoplastic Agents, PhytogenicAryl Hydrocarbon HydroxylasesColonColorectal NeoplasmsCytochrome P-450 CYP3ACytochrome P-450 Enzyme InhibitorsCytochrome P-450 Enzyme SystemDrug Resistance, NeoplasmFemaleHumansIn Vitro TechniquesKetoconazoleMaleMicrosomes, LiverMiddle AgedMutationNifedipineOxidoreductases, N-DemethylatingPaclitaxelRectum

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12237780

Citation

Martínez, C, et al. "Expression of Paclitaxel-inactivating CYP3A Activity in Human Colorectal Cancer: Implications for Drug Therapy." British Journal of Cancer, vol. 87, no. 6, 2002, pp. 681-6.
Martínez C, García-Martín E, Pizarro RM, et al. Expression of paclitaxel-inactivating CYP3A activity in human colorectal cancer: implications for drug therapy. Br J Cancer. 2002;87(6):681-6.
Martínez, C., García-Martín, E., Pizarro, R. M., García-Gamito, F. J., & Agúndez, J. A. (2002). Expression of paclitaxel-inactivating CYP3A activity in human colorectal cancer: implications for drug therapy. British Journal of Cancer, 87(6), 681-6.
Martínez C, et al. Expression of Paclitaxel-inactivating CYP3A Activity in Human Colorectal Cancer: Implications for Drug Therapy. Br J Cancer. 2002 Sep 9;87(6):681-6. PubMed PMID: 12237780.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Expression of paclitaxel-inactivating CYP3A activity in human colorectal cancer: implications for drug therapy. AU - Martínez,C, AU - García-Martín,E, AU - Pizarro,R M, AU - García-Gamito,F J, AU - Agúndez,J A G, PY - 2002/02/25/received PY - 2002/05/24/revised PY - 2002/05/29/accepted PY - 2002/9/19/pubmed PY - 2002/10/31/medline PY - 2002/9/19/entrez SP - 681 EP - 6 JF - British journal of cancer JO - Br J Cancer VL - 87 IS - 6 N2 - Cytochrome P450 3A is a drug-metabolising enzyme activity due to CYP3A4 and CYP3A5 gene products, that is involved in the inactivation of anticancer drugs. This study analyses the potential of cytochrome P450 3A enzyme in human colorectal cancer to impact anticancer therapy with drugs that are cytochrome P450 3A substrates. Enzyme activity, variability and properties, and the ability to inactivate paclitaxel (taxol) were analysed in human colorectal cancer and healthy colorectal epithelium. Cytochrome P450 3A enzyme activity is present in healthy and tumoral samples, with a nearly 10-fold interindividual variability. Nifedipine oxidation activity+/-s.d. for colorectal cancer microsomes was 67.8+/-36.6 pmol min(-1) mg(-1). The K(m) of the tumoral enzyme (42+/-8 microM) is similar to that in healthy colorectal epithelium (36+/-8 microM) and the human liver enzyme. Colorectal cancer microsomes metabolised the anticancer drug paclitaxel with a mean activity was 3.1+/-1.2 pmol min(-1) mg(-1). The main metabolic pathway is carried out by cytochrome P450 3A, and it is inhibited by the cytochrome P450 3A-specific inhibitor ketoconazole with a K(I) value of 31 nM. This study demonstrates the occurrence of cytochrome P450 3A-dependent metabolism in colorectal cancer tissue. The metabolic activity confers to cancer cells the ability to inactivate cytochrome P450 3A substrates and may modulate tumour sensitivity to anticancer drugs. SN - 0007-0920 UR - https://www.unboundmedicine.com/medline/citation/12237780/Expression_of_paclitaxel_inactivating_CYP3A_activity_in_human_colorectal_cancer:_implications_for_drug_therapy_ DB - PRIME DP - Unbound Medicine ER -