Steroidogenesis inhibitor

From Wikipedia, the free encyclopedia
Steroidogenesis inhibitor
Drug class
Class identifiers
SynonymsSteroid biosynthesis inhibitor; Steroid synthesis inhibitor
UseVarious
Biological targetSteroidogenic enzymes
Chemical classSteroidal; Nonsteroidal
In Wikidata

A steroidogenesis inhibitor, also known as a steroid biosynthesis inhibitor, is a type of drug which inhibits one or more of the enzymes that are involved in the process of steroidogenesis, the biosynthesis of endogenous steroids and steroid hormones.[1] They may inhibit the production of cholesterol and other sterols, sex steroids such as androgens, estrogens, and progestogens, corticosteroids such as glucocorticoids and mineralocorticoids, and neurosteroids.[1][2] They are used in the treatment of a variety of medical conditions that depend on endogenous steroids.[1]

Steroidogenesis inhibitors are analogous in effect and use to antigonadotropins (which specifically inhibit sex steroid production), but work via a different mechanism of action; whereas antigonadotropins suppress gonadal production of sex steroids by effecting negative feedback on and thereby suppressing the hypothalamic-pituitary-gonadal axis, steroidogenesis inhibitors directly inhibit the enzymatic biosynthesis of steroids.[1]

Types, examples, and uses[]

Cholesterol synthesis inhibitors[]

Cholesterol biosynthesis from acetyl-CoA.

Acetyl-CoA to lanosterol inhibitors[]

  • HMG-CoA reductase (HMGCR) inhibitors, also known as statins, prevent the conversion of HMG-CoA into mevalonic acid, a relatively early step in the biosynthesis of cholesterol from acetyl coenzyme A (acetyl-CoA), and thereby decrease cholesterol levels.[3] Examples of statins include atorvastatin, lovastatin, rosuvastatin, and simvastatin.[3] They are used in the treatment of hypercholesterolemia for the purpose of lowering the risk of atherosclerosis-related cardiovascular disease.[3]
  • Farnesyl pyrophosphate synthase (FPPS) inhibitors prevent the conversion of isopentenyl pyrophosphate (IPP) into farnesyl pyrophosphate (FPP), a mid-range step in the biosynthesis of cholesterol from acetyl-CoA, and thereby inhibit cholesterol production.[4][5] They notably do not significantly lower circulating levels of cholesterol however, and hence, unlike statins, are not suitable for the treatment of hypercholesterolemia.[6] The main examples of FPPS inhibitors are nitrogenous bisphosphonates such as alendronate, ibandronate, pamidronate, risedronate, and zoledronate, which are used in the treatment of osteoporosis.[4][5]

Lanosterol to cholesterol inhibitors[]

  • 7-Dehydrocholesterol reductase (7-DHCR) inhibitors such as and inhibit the production of cholesterol from 7-dehydrocholesterol, one of the last steps in cholesterol biosynthesis.[10][11] Loss-of-function mutations in the gene encoding 7-DHCR result in Smith–Lemli–Opitz syndrome (SLOS) and dramatic accumulation of 7-dehydrocholesterol.[10][11] 7-DHCR inhibitors produce an acquired form of SLOS in animals, and as such, like 24-DHCR inhibitors (see below), are probably too toxic to be used clinically.[10][11]
  • 24-Dehydrocholesterol reductase (24-DHCR) inhibitors such as azacosterol and triparanol inhibit the production of cholesterol from desmosterol, one of the last steps in cholesterol biosynthesis, and were formerly used to treat hypercholesterolemia, but were withdrawn from the market due to toxicity caused by accumulation of desmosterol in tissues.[12][13]

Steroid hormone synthesis inhibitors[]

Steroidogenesis, biosynthesis of steroid hormones from cholesterol.[14]

Non-specific steroid hormone synthesis inhibitors[]

Corticosteroid-specific synthesis inhibitors[]

  • Aldosterone synthase (CYP11B2) inhibitors such as metyrapone,[26] mitotane,[16] and osilodrostat[25] prevent the production of the potent mineralocorticoid aldosterone from the less potent mineralocorticoid corticosterone.[17] Osilodrostat was investigated for the treatment of hypertension, heart failure, and renal disease, but development for these indications was discontinued.[25]

Sex steroid-specific synthesis inhibitors[]

  • 17β-Hydroxysteroid dehydrogenase (17β-HSD) inhibitors prevent the reversible conversion of the weak androgens dehydroepiandrosterone (DHEA) and 4-androstenedione into the more potent androgen testosterone and the weak estrogen estrone into the more potent estrogen estradiol.[27]

Other steroid synthesis inhibitors[]

  • Lanosterol 14α-demethylase (CYP51A1) inhibitors such as clotrimazole, fluconazole, itraconazole, ketoconazole, miconazole, and voriconazole prevent the production of ergosterol from lanosterol.[17][37] Ergosterol is absent in animals but is an essential component of the cell membranes of many fungi and protozoa, and so lanosterol 14α-demethylase inhibitors are used as antifungals and antiprotozoals in the treatment of infections.[37]

List of steroid metabolism modulators[]

Enzyme Substrates→Products Inhibitors Inducers
HMG-CoA reductase
(HMGCR) 		HMG-CoA→Mevalonic acid Atorvastatin • Cerivastatin • Colestolone • Fluvastatin • Lovastatin • Mevastatin • Pitavastatin • Pravastatin • Rosuvastatin • Simvastatin
FPPS Dimethylallyl pyrophosphate (isoprenyl pyrophosphate)→Farnesyl pyrophosphate • Isopentenyl pyrophosphate→Farnesyl pyrophosphate Alendronic acid • Ibandronic acid • Incadronic acid • Pamidronic acid • Risedronic acid • Zoledronic acid
7-DHCR 7-Dehydrocholesterol→Cholesterol • • Triparanol
24-DHCR Desmosterol→Cholesterol Azacosterol • Clomifene • Triparanol •
P450scc
(CYP11A1) 		Cholesterol→22R-Hydroxycholesterol • 22R-Hydroxycholesterol→20α,22R-Dihydroxycholesterol • 20α,22R-Dihydroxycholesterol→Pregnenolone • • • Aminoglutethimide • Amphenone B • Canrenone • Cyanoketone • Danazol • Etomidate • Ketoconazole • Levoketoconazole • Mitotane • Spironolactone • Trilostane
3β-HSD
(HSD3B) 		Pregnenolone→Progesterone • 17α-Hydroxypregnenolone→17α-Hydroxyprogesterone • Dehydroepiandrosterone→Androstenedione • 5-Androstenediol→Testosterone • Androstadienol→Androstadienone • Δ4-Abiraterone • Abiraterone • Abiraterone acetate • Amphenone B • Azastene • Cyanoketone • Cyproterone acetate • Danazol • Epostane • Genistein • Gestrinone • Medrogestone • Medroxyprogesterone acetate • Metribolone • Metyrapone • Norethisterone • Oxymetholone • Pioglitazone • Rosiglitazone • Trilostane • Troglitazone
17α-Hydroxylase,
17,20-lyase (CYP17A1) 		Pregnenolone→17α-Hydroxypregnenolone • Progesterone→17α-Hydroxyprogesterone • 17α-Hydroxypregnenolone→Dehydroepiandrosterone • 17α-Hydroxyprogesterone→Androstenedione • • Δ4-Abiraterone • Abiraterone • Abiraterone acetate • Amphenone B • Bifluranol • Bifonazole • Canrenone • • Clotrimazole • Cyanoketone • Cyproterone acetate • Danazol • Econazole • Etomidate • Flutamide • Galeterone • Gestrinone • Isoconazole • Ketoconazole • • Levoketoconazole • Liarozole • • • Miconazole • Mifepristone • Nilutamide • Orteronel • Pioglitazone • Prochloraz • Rosiglitazone • Seviteronel • Spironolactone • Stanozolol • • • TGF-β • Tioconazole • Troglitazone • •
11β-HSD
(HSD11B) 		Cortisol↔Cortisone 11-Ketoprogesterone • 11α-Hydroxyprogesterone • 11β-Hydroxyprogesterone • • • Acetoxolone • Amphenone B • Carbenoxolone • Enoxolone (glycyrrhetinic acid) • Epigallocatechin gallate • Glycyrrhizin (glycyrrhizic acid) (licorice) • Progesterone
21-Hydroxylase
(CYP21A2) 		Progesterone→11-Deoxycorticosterone • 17α-Hydroxyprogesterone→11-Deoxycortisol Aminoglutethimide • Amphenone B • Bifonazole • Canrenone • Clotrimazole • Diazepam • Econazole • Genistein • Isoconazole • Ketoconazole • Levoketoconazole • Metyrapone • Miconazole • Midazolam • Spironolactone • Abiraterone • Abiraterone acetate • Tioconazole
11β-Hydroxylase
(CYP11B1) 		11-Deoxycorticosterone→Corticosterone • 11-Deoxycortisol→Cortisol Δ4-Abiraterone • Abiraterone • Abiraterone acetate • Aminoglutethimide • Canrenone • Etomidate • Fadrozole • • Ketoconazole • Levoketoconazole • Metomidate • • Metyrapone • Mitotane • Potassium canrenoate • Spironolactone • Trilostane• Osilodrostat
Aldosterone
synthase (CYP11B2) 		Corticosterone→Aldosterone • • Aminoglutethimide • Azelnidipine • Benidipine • Canrenone • Cilnidipine • Efonidipine • • Fadrozole • Ketoconazole • Metyrapone • Mespirenone • Osilodrostat • Potassium canrenoate • Spironolactone
17β-HSD
(HSD17B) 		Dehydroepiandrosterone↔5-Androstenediol • Androstenedione↔Testosterone • Estrone↔Estradiol Danazol • Ethanol • Fisetin • • Simvastatin • • •
5α-Reductase
(SRD5A) 		→ • Progesterone→5α-Dihydroprogesterone • 3α-Dihydroprogesterone→Allopregnanolone • 3β-Dihydroprogesterone→Isopregnanolone • Deoxycorticosterone→5α-Dihydrodeoxycorticosterone • Corticosterone→5α-Dihydrocorticosterone • Cortisol→5α-Dihydrocortisol • Aldosterone→5α-Dihydroaldosterone • Androstenedione→5α-Androstanedione • Testosterone→5α-Dihydrotestosterone • Androstadienone→Androstenone • Δ4-Abiraterone • Abiraterone • Abiraterone acetate • Alfatradiol • Azelaic acid • β-Sitosterol • Bexlosteride • Chlormadinone acetate • Cl-4AS-1 • Dutasteride • Epitestosterone • Epristeride • Fatty acids (α-linolenic acid, linoleic acid, γ-linolenic acid, , oleic acid) • Finasteride • Ganoderic acid • Gestodene • Izonsteride • • Lapisteride • Oxendolone • Saw palmetto extract • TFM-4AS-1 • Turosteride • Vitamin B6 • Zinc
3α-HSD
(AKR1C4) 		5α-Dihydroprogesterone↔Allopregnanolone • DHDOC↔THDOC • Dihydrotestosterone↔3α-Androstanediol Coumestrol • Daidzein • Genistein • Indometacin • Medroxyprogesterone acetate Fluoxetine • Fluvoxamine • Mirtazapine • Paroxetine • Sertraline • Venlafaxine
Aromatase
(CYP19A1) 		16α-Hydroxyandrostenedione→16α-Hydroxyestrone • Androstenedione→Estrone • Nandrolone→Estradiol • Metandienone→Methylestradiol • Methyltestosterone→Methylestradiol • Testosterone→Estradiol 4-AT • • 4'-Hydroxynorendoxifen • 4-Hydroxytestosterone • 5α-DHNET • 20α-Dihydroprogesterone • • alpha-Naphthoflavone • Aminoglutethimide • Anastrozole • Ascorbic acid (vitamin C) • Atamestane • ATD • Bifonazole • • • Chalconoids (e.g., isoliquiritigenin) • Clotrimazole • • Coumestrol • DHT • • Econazole • Ellagitannins • Endosulfan • Exemestane • Fadrozole • Fatty acids (e.g., conjugated linoleic acid, linoleic acid, linolenic acid, palmitic acid) • Fenarimol • Finrozole • Flavonoids (e.g., , , 7,8-DHF, acacetin, apigenin, baicalein, biochanin A, chrysin, EGCG, gossypetin, hesperetin, liquiritigenin, myricetin, naringenin, pinocembrin, rotenone, quercetin, sakuranetin, tectochrysin) • Formestane • Imazalil • Isoconazole • Ketoconazole • Leflutrozole • Letrozole • Liarozole • Melatonin • • Miconazole • Minamestane • Nimorazole • • Norendoxifen • • • Phenytoin • PGE2 (dinoprostone) • Plomestane • Prochloraz • Propiconazole • Quinolinoids (e.g., berberine, , , , , ) • Resorcylic acid lactones (e.g., zearalenone) • Rogletimide (pyridoglutethimide) • Stilbenoids (e.g., resveratrol) • Terpenoids (e.g., , , retinol (vitamin A), Δ9-THC, tretinoin) • Testolactone • Tioconazole • Triadimefon • • Troglitazone • Valproic acid • Vorozole • Xanthones (e.g., , , , , , ) • • Zinc Atrazine • Flavonoids (e.g., genistein, quercetin)
SST/EST Dehydroepiandrosterone→Dehydroepiandrosterone sulfate • Estrone→Estrone sulfate • 6-Hydroxyflavone • • 7,8-Dihydroxyflavone • Equol • Galangin • Genistein • Parabens (e.g., butylparaben) • Pentachlorophenol (PCP) • Triclosan
STS Cholesterol sulfate→Cholesterol • Dehydroepiandrosterone sulfate→Dehydroepiandrosterone • Estrone sulfate→Estrone • Pregnenolone sulfate→Pregnenolone • Danazol • Estradiol sulfamate (E2MATE) • Estrone sulfamate (EMATE) • Irosustat (STX64, 667 Coumate, BN-83495) • • • • •
Sterol
27-hydroxylase
(CYP27A1) 		Cholesterol→27-Hydroxycholesterol Anastrozole • Bicalutamide • Dexmedetomidine • Fadrozole • Posaconazole • Ravuconazole
Cholesterol
7α-hydroxylase (CYP7A1) 		Cholesterol→7α-Hydroxycholesterol (intermediate to bile acids) Ketoconazole • Levoketoconazole
Lanosterol
14α-demethylase (CYP51A1) 		Lanosterol→ (intermediate to ergosterol) Albaconazole • • • • • Azalanstat • • Bifonazole • • Butoconazole • Chlormidazole • • Clotrimazole • Croconazole • Cyproconazole • • • • Eberconazole • Econazole • Econazole/triamcinolone • Efinaconazole • • Enilconazole • • Fenticonazole • Fluconazole • Flutrimazole • Fosfluconazole • • Hexaconazole • Isavuconazole • • Isavuconazonium sulfate • Isoconazole • Itraconazole • Ketoconazole • • Levoketoconazole • Luliconazole • Miconazole • Neticonazole • Omoconazole • • Oxiconazole • • • Posaconazole • Propiconazole • Pramiconazole • • Ravuconazole • • Sertaconazole • Sulconazole • Tebuconazole • Terconazole (triaconazole) • Tioconazole • Uniconazole • • Voriconazole • •


See also[]

References[]

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