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
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.