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Abstract
Galeterone and abiraterone acetate are antiandrogens developed for the treatment of metastatic castration-resistant prostate cancer. In the present study, we investigated the effect of these drugs on dehydroepiandrosterone (DHEA) sulfonation catalyzed by human liver and intestinal cytosols and human recombinant sulfotransferase enzymes (SULT2A1, SULT2B1b, and SULT2E1) and compared their effects to those of other antiandrogens (cyproterone acetate, spironolactone, and danazol). Each of these chemicals (10 μM) inhibited DHEA sulfonation catalyzed by human liver and intestinal cytosols. Enzyme kinetic analysis showed that galeterone and abiraterone acetate inhibited human liver cytosolic DHEA sulfonation with apparent Ki values at submicromolar concentrations, whereas cyproterone acetate, spironolactone, and danazol inhibited it with apparent Ki values at low micromolar concentrations. The temporal pattern of abiraterone formation and abiraterone acetate depletion suggested that the metabolite abiraterone, not the parent drug abiraterone acetate, was responsible for the inhibition of DHEA sulfonation in incubations containing human liver cytosol and abiraterone acetate. Consistent with this proposal, similar apparent Ki values were obtained, regardless of whether abiraterone or abiraterone acetate was added to the enzymatic incubation. Abiraterone was more effective than abiraterone acetate in inhibiting DHEA sulfonation when catalyzed by human recombinant SULT2A1 or SULT2B1b. In conclusion, galeterone and abiraterone are novel inhibitors of DHEA sulfonation, as determined in enzymatic incubations containing human tissue cytosol (liver or intestinal) or human recombinant SULT enzyme (SULT2A1, SULT2B1b, or SULT1E1). Our findings on galeterone and abiraterone may have implications in drug-drug interactions and biosynthesis of steroid hormones.
Footnotes
- Received October 16, 2017.
- Accepted February 2, 2018.
This research was supported by the Singapore Ministry of Education Academic Research Fund Tier 1 [Grant R-148-000-218-112 to A.J.L.], the National University of Singapore [Start-Up Grant R-148-000-185-133 to A.J.L.], and the Singapore Ministry of Health’s National Medical Research Council under its Cooperative Basic Research Grant scheme [Grant R-148-000-225-511 to A.J.L.]. S.B. was supported by a National University of Singapore Research Scholarship.
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- Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics
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