ABSTRACT
The recent identification of tetrahydrogestrinone (THG), a non-marketed designer androgen used for sports doping but previously undetectable by established mass spectrometry-based urine drug screens, and its production by a facile chemical modification of gestrinone has raised concerns about the risks of developing designer androgens from numerous marketed progestins. We therefore have used yeast-based in vitro androgen and progesterone bioassays to conduct a structure-activity study assessing the intrinsic androgenic potential of commercially available progestins and their derivatives, to identify those compounds or structures with the highest risk of forming a basis for such misapplication. Progestins had a wide range of androgenic bioactivity that was not reliably predicted for individual steroids by their progestin bioactivity. 17alpha-Hydroxyprogesterone and 19-norprogesterone derivatives with their bulky 17beta-substituents were strong progestins but generally weak androgens. 17alpha-Ethynylated derivatives of testosterone, 19-nortestosterone and 18-methyl-19-nortestosterone such as gestrinone, ethisterone, norethisterone and norgestrel had the most significant intrinsic androgenicity of all the commercially marketed progestins. Facile chemical modification of the 17alpha-ethynyl group of each of these progestins produces 17alpha-methyl, ethyl and allyl derivatives, including THG and norbolethone, which further enhanced androgenic bioactivity. Thus by using the rapid and sensitive yeast bioassay we have screened a comprehensive set of progestins and associated structures and identified the ethynylated testosterone, 19-nortestosterone and 18-methyl-19-nortestosterone derivatives as possessing the highest risk for abuse and potential for conversion to still more potent androgens. By contrast, modern progestins such as progesterone, 17alpha-hydroxyprogesterone and 19-norprogesterone derivatives had minimal androgenic bioactivity and pose low risk.
Subject(s)
Androgens/metabolism , Progestins/metabolism , Yeasts/metabolism , Androgens/chemistry , Androgens/pharmacology , Biological Assay/methods , Dose-Response Relationship, Drug , Ethisterone/chemistry , Ethisterone/metabolism , Ethisterone/pharmacology , Gestrinone/chemistry , Gestrinone/metabolism , Gestrinone/pharmacology , Molecular Structure , Norethindrone/chemistry , Norethindrone/metabolism , Norethindrone/pharmacology , Norgestrel/chemistry , Norgestrel/metabolism , Norgestrel/pharmacology , Norpregnenes/chemistry , Norpregnenes/metabolism , Norpregnenes/pharmacology , Norprogesterones/chemistry , Norprogesterones/metabolism , Norprogesterones/pharmacology , Progestins/chemistry , Progestins/pharmacology , Receptors, Androgen/metabolism , Receptors, Progesterone/metabolism , Structure-Activity Relationship , Yeasts/drug effectsABSTRACT
The alimentary canal of the larval mosquito displays a considerable degree of physiological compartmentalization among its different anatomical sub-divisions (gastric caeca, anterior midgut, posterior midgut and hindgut). We performed a comparative microarray analysis in order to identify transcripts which are particularly enriched in each gut section. Based on the available annotation of the selected transcripts, we suggest that the metabolism and absorption of proteins and carbohydrates takes place mainly in the gastric caeca and posterior midgut, whereas the anterior midgut specializes in the metabolism and absorption of lipids. Transcripts encoding antimicrobial peptides were found to be enriched in the gastric caeca, and a high enrichment of transcripts associated with enzymes involved in xenobiotic detoxification was found in the anterior midgut. Furthermore, our data support the notion that the region encompassing the hindgut and Malpighian tubes plays important roles in avoiding the excretion of nutrients, as well as in xenobiotic detoxification.
