Expression of paclitaxel-inactivating CYP3A activity in human colorectal cancer: implications for drug therapy.
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.
Martínez
C
C
Department of Pharmacology, Medical School, University of Extremadura, Avda. de Elvas s/n, E-06071, Badajoz, Spain.
García-Martín
E
E
Pizarro
R M
RM
García-Gamito
F J
FJ
Agúndez
J A G
JA
D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases; D003106:Colon / Q000201:enzymology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007654:Ketoconazole / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D008875:Middle Aged; D009154:Mutation; D009543:Nifedipine / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017239:Paclitaxel / Q000378:metabolism / Q000494:pharmacology*; D012007:Rectum / Q000201:enzymology
D000972:Antineoplastic Agents, Phytogenic; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D009543:Nifedipine; D017239:Paclitaxel; D007654:Ketoconazole