Cytochrome P450CYP1B1 protein expression: a novel mechanism of anticancer drug resistance

McFadyen, MCE McLeod, HL Jackson, FC Melvin, WT Doehmer, J Murray, GI

Mce. Mcfadyen et al., Cytochrome P450CYP1B1 protein expression: a novel mechanism of anticancer drug resistance, BIOCH PHARM, 62(2), 2001, pp. 207-212

34

INGLESE

Article

Pharmacology & Toxicology

BIOCHEMICAL PHARMACOLOGY

0006-2952 → ACNP

62

2

2001

207 - 212

ISI

0006-2952(20010715)62:2<207:CPPEAN>2.0.ZU;2-5

The overexpression of human cytochrome P450 CYP1B1 has been observed in a w ide variety of malignant tumours, but the protein is undetectable in normal tissues. A number of cytochrome P450 enzymes are known to metabolise a var iety of anticancer drugs, and the consequence of cytochrome P450 metabolism is usually detoxification of the drug, although bioactivation occurs in so me cases. in this study, a Chinese hamster ovary cell line expressing human cytochrome P450 CYP1B1 was used to evaluate the cytotoxic profile of sever al anticancer drugs (docetaxel, paclitaxel, cyclophosphamide, doxorubicin, 5-fluorouracil, cisplatin, and carboplatin) commonly used clinically in the treatment of cancer. The MTT (3-[4,5-dimethylthiazol-2yl]-2,5-diphenyltetr azolium bromide) as say was used to determine the levels of cytotoxicity. T he key finding of this study was that on exposure to docetaxel, a significa nt decrease in sensitivity towards the cytotoxic effect's of docetaxel was observed in the cell line expressing CYP1B1 compared to the parental cell l ine (P = 0.03). Moreover, this difference in cytotoxicity was reversed by c o-incubation of the cells with both docetaxel and the cytochrome P450 CYP1 inhibitor alpha-naphthoflavone. This study is the first to indicate that th e presence of CYP1B1 in cells decreases their sensitivity to the cytotoxic effects of a specific anticancer drug. (C) 2001 Elsevier Science Inc. All r ights reserved.