The environmental toxin 2,3,7,8-tetrachlorodibenzo-p-dioxin induces cytochrome P450 activity in high passage PC 3 and DU 145 human prostate cancer cell lines.
The study was conducted to investigate whether 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces cytochrome P450 (CYP) 1A1 and CYP1B1 via the aryl hydrocarbon receptor (AhR) in the hormone-independent human prostate cancer cell lines PC 3 and DU 145. No quantitative differences in the expression of AhR and its partner transcription factor ARNT were seen in low and high passage number PC 3 and DU 145 cells in the absence and presence of TCDD as assessed by RT-PCR and Western blotting. However, CYP1A1/1B1 activity, measured by the 7-ethoxyresorufin-O-deethylase (EROD) assay, was induced by 10 and 100 nM TCDD only in high passage number PC 3 and DU 145 cells (PC 3, 7.7- and 2-fold stimulation; DU 145, 8.5- and 19.7-fold stimulation). Besides stimulation of EROD activity, induction of the expression of CYP1A1 and, to a lesser extend, of CYP1B1 by TCDD was also demonstrated by RT-PCR and Western blotting. However, 1-100 nM TCDD did not significantly alter cell cycle distribution and cell growth for up to five days. The induction of CYP1A1 and CYP1B1 by TCCD in the hormone-independent prostate cancer cell lines suggests that CYP induction should be considered in patients with advanced prostate cancer. This could result in higher elimination rates of concomitant drugs metabolized by these particular CYP isoenzymes.
Schaufler
Katharina
K
Department of Pathophysiology, University of Vienna, A-1090 Vienna, Austria.
Haslmayer
Petra
P
Jäger
Walter
W
Pec
Martina
M
Thalhammer
Theresia
T
D001189:Aryl Hydrocarbon Hydroxylases; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D002455:Cell Division; D019363:Cytochrome P-450 CYP1A1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins; D004347:Drug Interactions; D004785:Environmental Pollutants / Q000633:toxicity*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008297:Male; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
C497396:ARNT protein, human; D004268:DNA-Binding Proteins; D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1