INVOLVEMENT OF HUMAN CYTOCHROMES P450 (CYP) IN THE REDUCTIVE METABOLISM OF AQ4N, A HYPOXIA ACTIVATED ANTHRAQUINONE DI-N-OXIDE PRODRUG

Citation
Sm. Raleigh et al., INVOLVEMENT OF HUMAN CYTOCHROMES P450 (CYP) IN THE REDUCTIVE METABOLISM OF AQ4N, A HYPOXIA ACTIVATED ANTHRAQUINONE DI-N-OXIDE PRODRUG, International journal of radiation oncology, biology, physics, 42(4), 1998, pp. 763-767
Citations number
35
Categorie Soggetti
Oncology,"Radiology,Nuclear Medicine & Medical Imaging
ISSN journal
03603016
Volume
42
Issue
4
Year of publication
1998
Pages
763 - 767
Database
ISI
SICI code
0360-3016(1998)42:4<763:IOHCP(>2.0.ZU;2-J
Abstract
Purpose: To establish the role of the human cytochromes P450 (CYPs) in the reductive metabolism of the novel anthraquinone di-N-oxide prodru g AQ4N. Methods and Materials: Metabolism of AQ4N was conducted in a p anel of 17 human phenotyped liver microsomes. AQ4N and metabolites wer e detected by reverse phase isocratic HPLC. CYP inhibitors and Spearma n rank correlation were used to determine the significance of AQ4N met abolism versus specific CYP activity and/or expression. Results: Anaer obic metabolism of AQ4N to the 2-electron reduction product, AQM, and the 4-electron reduced tertiary amine, AQ4, occurred in all 17 human l iver microsome preparations. The range (+/- SE) for total AQ4N turnove r was 14.26 +/- 1.43 nmol/incubate (highest) to 3.65 +/- 1.05 nmol/inc ubate (lowest). Metabolism was not detected in the absence of NADPH or microsomes. In aerobic incubates, AQM was less than 4% of anaerobic v alues whereas AQ4 was undetectable. CYP-mediated metabolism of AQ4N wa s inhibited completely by ketoconazole (KET) and carbon monoxide (CO), two global inhibitors of CYP-mediated metabolism. AQ4N metabolism cor related significantly with probes for CYP 3A, specifically benzoxylres orufin O-dealkylation [r(s) = 0.70, p < 0.01] and tamoxifen N-demethyl ation (r(s) = 0.85, p < 0.01), but not with probes for CYPs 2C, 2D, an d 1A. CYP 3A involvement was confirmed by the use of the CYP 3A specif ic inhibitor, triacetyloleandomycin (TAO), which repressed the formati on of AQM to 13% of the uninhibited value and abolished completely the formation of AQ4. Alpha-naphthoflavone (ANF), an inhibitor of CYP 2C and 1A, had no significant effect on AQ4N metabolism. Conclusions: The se data suggest that the human CYP 3A enzymes can contribute to the re ductive metabolism of AQ4N CYP 3A enzymes are highly expressed in a br oad spectrum of human cancers. The results show that AQ4N requires ana erobic conditions for CYP 3A-mediated reduction and hence this subfami ly of enzymes is likely to selectively activate AQ4N in hypoxic tumors . (C) 1998 Elsevier Science Inc.