Involvement of human cytochromes P450 (CYP) in the reductive metabolism of AQ4N,a hypoxia activated anthraquinone DI-N-oxide prodrug |
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| Affiliation: | 1. Department of Pharmaceutical Sciences, De Montfort University, Leicester, United Kingdom;2. School of Biomedical Sciences, University of Ulster at Jordanstown, N. Ireland, Ireland;1. Department of Botanical and Environmental Sciences, Guru Nanak Dev University, Amritsar 143005, Punjab, India;2. Akal College of Basic Sciences (Botany), Eternal University, Baru Sahib, Sirmour 173101, Himachal Pradesh, India;3. Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar 143005, Punjab, India;1. Center for Reproductive Medicine, Shandong University, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, PR China;2. The Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, PR China;3. Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA;4. Center for Reproductive Medicine, Tai''an Central Hospital, Tai''an, PR China;5. The Chinese University of Hong Kong-Shandong University Joint Laboratory on Reproductive Genetics, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, PR China;1. Department of General Surgery, Shandong University Qilu Hospital, Jinan, Shandong 250012, China;2. Department of General Surgery, Qihe People''s Hospital, Qihe, Shandong 251100, China;3. Department of General Surgery, Licheng District People''s Hospital, Jinan, Shandong 250115, China;4. Department of General Surgery, Caoxian People''s Hospital, Caoxian, Shandong 274400, China |
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| Abstract: | ![]()
Purpose: To establish the role of the human cytochromes P450 (CYPs) in the reductive metabolism of the novel anthraquinone di-N-oxide prodrug AQ4N.Methods and Materials: Metabolism of AQ4N was conducted in a panel of 17 human phenotyped liver microsomes. AQ4N and metabolites were detected by reverse phase isocratic HPLC. CYP inhibitors and Spearman rank correlation were used to determine the significance of AQ4N metabolism versus specific CYP activity and/or expression.Results: Anaerobic metabolism of AQ4N to the 2-electron reduction product, AQM, and the 4-electron reduced tertiary amine, AQ4, occurred in all 17 human liver microsome preparations. The range (± SE) for total AQ4N turnover was 14.26 ± 1.43 nmol/incubate (highest) to 3.65 ± 1.05 nmol/incubate (lowest). Metabolism was not detected in the absence of NADPH or microsomes. In aerobic incubates, AQM was less than 4% of anaerobic values whereas AQ4 was undetectable. CYP-mediated metabolism of AQ4N was inhibited completely by ketoconazole (KET) and carbon monoxide (CO), two global inhibitors of CYP-mediated metabolism. AQ4N metabolism correlated significantly with probes for CYP 3A, specifically benzoxylresorufin O-dealkylation [r(s) = 0.70, p <0.01] and tamoxifen N-demethylation (r(s) = 0.85, p < 0.01), but not with probes for CYPs 2C, 2D, and 1A. CYP 3A involvement was confirmed by the use of the CYP 3A specific inhibitor, triacetyloleandomycin (TAO), which repressed the formation 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: These data suggest that the human CYP 3A enzymes can contribute to the reductive metabolism of AQ4N. CYP 3A enzymes are highly expressed in a broad spectrum of human cancers. The results show that AQ4N requires anaerobic conditions for CYP 3A-mediated reduction and hence this subfamily of enzymes is likely to selectively activate AQ4N in hypoxic tumors. |
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