AKR1C3
aldo-keto reductase family 1 member C3
Theoretical — per Powers
Gene summary
A protein-coding gene on chromosome 10 (steroid hormone synthesis, steroid conjugation and clearance). Encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and proteins. These enzymes catalyze the conversion of aldehydes and ketones to their corresponding alcohols by utilizing NADH and/or NADPH as cofactors.
Source: NCBI Gene, accessed 2026-10-07.
Protein reference (UniProt)
- Protein
Aldo-keto reductase family 1 member C3
- Function (excerpt)
Cytosolic aldo-keto reductase that catalyzes NADPH-dependent reduction of ketosteroids to hydroxysteroids. Displays broad substrate specificity with distinct positional and stereochemistry, primarily generating 17beta-hydroxysteroids, but also 3alpha- and 20alpha-hydroxysteroids. Produces potent androgens via classical and 'backdoor'/alternative pathways. In the classical androgen metabolic pathway (biosynthesis of 5alpha-dihydrotestosterone (5alpha-DHT) via testosterone), catalyzes the reduction of delta4-androstenedione to form testosterone. In the 'backdoor' androgen metabolic pathway (biosynthesis of 5alpha-dihydrotestosterone (5alpha-DHT) via pregnanes), reduces androsterone to 5alpha-androstane-3alpha,17beta-diol preceding 5alpha-DHT secretion. Reduces 5alpha-DHT to less potent androgen 5alpha-androstane-3alpha,17beta-diol, likely regulating ligand availability for androgen receptors. May contribute to the metabolism of adrenal-derived androgen precursors.
- Subcellular location
Cytoplasm.
- Tissue specificity
Expressed in many tissues including adrenal gland, brain, kidney, liver, lung, mammary gland, placenta, small intestine, colon, spleen, prostate and testis. High expression in prostate and mammary gland. In the prostate, higher levels in epithelial cells than in stromal cells. In the brain, expressed in medulla, spinal cord, frontotemporal lobes, thalamus, subthalamic nuclei and amygdala. Weaker expression in the hippocampus, substantia nigra and caudate.
Source: UniProtKB/Swiss-Prot P42330, release 2026_03, licensed CC BY 4.0. This is the protein’s normal biology, not evidence about post-drug syndromes; associated conditions are inherited disorders of the gene, not PFS, PSSD or PRSD.
Why its pathway is in the library
Steroid-synthesis enzymes sit directly on the pathways perturbed by 5-alpha-reductase inhibitors and SSRIs; inherited variation here is a candidate susceptibility factor for persistent post-drug phenotypes. Steroid clearance is the exit route for androgens and their metabolites — the pathway at the center of Powers' PFS model (defective glucuronidation/sulfation trapping androgens intracellularly). Gut bacterial enzymes can undo this clearance, linking it to the microbiome thread.
Written for the whole steroid synthesis / conjugation & clearance / retinoid signaling family, not for AKR1C3 specifically.
Powers’ note (his unpublished theorizing)
Named by Powers (DWP-001; DWP-003, unpublished) as part of the AKR1C cluster in his susceptibility model; broadest substrate range of the four isoforms (androgens, estrogens, progesterone, prostaglandins).
Narrative library record
Function
3-alpha-hydroxysteroid dehydrogenase type 2 (also 17-beta-hydroxysteroid dehydrogenase type 5); metabolizes prostaglandins, estrogens, and progesterone in addition to androgens, and is overexpressed in prostate cancer. Broadest substrate range of the four AKR1C isoforms.
Corpus relevance
Included as part of the AKR1C cluster Powers implicates in his susceptibility model (DWP-001); its prostaglandin and estrogen/progesterone activity widens the candidate pathways beyond pure androgen metabolism. Less specifically discussed than AKR1C2 in Powers' posts. Attribution: theoretical-per-Powers.
Powers’ claims naming AKR1C3
- Powers gene claim
AKR1C1; AKR1C2; AKR1C3; AKR1C4 — defects (unspecified)
Confidence: direct
Defects in AKR1C enzymes can contribute, but their products are mostly cleared via glucuronidation — so a bad glucuronidation enzyme (UGT2B1X) is the more fundamental defect. AKR1C enzymes and SRD5A1 are also epigenetically silenceable, and valproic acid may…
AKR1C1AKR1C2AKR1C3AKR1C4SRD5A1PGL-AKR1C1-AKR1C2-AKR1C3-AKR1C4circa May 2026PFS
Mentioned in 7 corpus records
- Powers · Reddit post
I think I have figured out at least one specific phenotype of PFS, and it is different from the "allopregnanolone" theory
u/drwillpowers · r/DrWillPowers
Powers' key genetics-first post: he proposed a specific PFS phenotype whose "base, core defect" is defective UGT2B17, disabling testosterone's main glucuronidation exit pathway. Carriers show shockingly low 3α-androstanediol glucuronide and near-zero urinary…
AKR1C1AKR1C2AKR1C3AKR1C4HSD17B2+3DWP-0032026PFSCore corpus - Powers · Reddit commentCurated Powers pick
Re: The Problems with the Theory of Impaired Androgen Signaling caused by Metabolite Accumulation: A Peaceful Challenge to Dr. Powers’ Thesis
u/drwillpowers · r/DrWillPowers
Long reply to a community member's critique of his impaired-androgen-signaling theory. Powers concedes his earlier strong claim — that androgens must exit through DHT when UGTs are impaired — was overstated: testosterone can route through oxidation…
AKR1C3ARUGT2B17PRH-01172026-09-20T19:15:54ZPFSPowers Reddit history - Powers · Reddit commentCurated Powers pick
Powers explained his use of indomethacin as the only available "hammer" for lowering THDOC, while noting he lacks good alternatives — one patient with a single kidney cannot take NSAIDs, diazepam inhibits THDOC synthesis but is itself a GABA-A agonist…
AKR1C3PRH-01592026-09-12T18:10:57ZPFSPSSDPowers Reddit history - Gene recordPowers’ theory
AKR1C1 — aldo-keto reductase family 1 member C1
10p15-p14 (AKR1C gene cluster, chromosome 10)
Cytosolic NAD(P)H-dependent oxidoreductase with mainly 20-alpha-hydroxysteroid dehydrogenase activity; converts progesterone to the inactive 20-alpha-hydroxyprogesterone and also reduces a range of aldehydes, ketones, and xenobiotics. One of four closely…
AKR1C1AKR1C2AKR1C3AKR1C4SRD5A1+1GENE-AKR1C1PFSCore corpus - Gene recordPowers’ theory
AKR1C2 — aldo-keto reductase family 1 member C2
10p15-p14 (AKR1C gene cluster, chromosome 10)
3-alpha-hydroxysteroid dehydrogenase type 3; interconverts DHT and the much weaker 5-alpha-androstane-3-alpha,17-beta-diol (3-alpha-diol), effectively switching DHT's androgenic signal off, and participates in synthesis of neurosteroids such as…
AKR1C1AKR1C2AKR1C3AKR1C4AR+1GENE-AKR1C2PFSCore corpus - Gene recordPowers’ theory
AKR1C4 — aldo-keto reductase family 1 member C4
10p15-p14 (AKR1C gene cluster, chromosome 10)
3-alpha-hydroxysteroid dehydrogenase type 1; liver-restricted isoform that reduces 3-keto-5-dihydrosteroids to tetrahydro products and participates in neurosteroid synthesis. Loss of AKR1C4 alone does not cause developmental phenotypes but can worsen the…
AKR1C1AKR1C2AKR1C3AKR1C4UGT1A1+1GENE-AKR1C4Core corpus - Gene record
Aromatase - the P450 enzyme catalyzing the final steps of estrogen biosynthesis, converting androgens (testosterone, androstenedione) to estrogens (estradiol, estrone). Tissue-specific promoters drive expression in placenta, gonads, adipose, and brain…
AKR1C3ARCYP17A1CYP19A1HSD3B2GENE-CYP19A1PFSPSSDCore corpus
Also in steroid hormone synthesis
All 38 genes- SRD5A2
steroid 5 alpha-reductase 2
chr 2· Steroid synthesis· 19 records - SRD5A1Powers
steroid 5 alpha-reductase 1
chr 5· Steroid synthesis· 17 records - AKR1C2Powers
aldo-keto reductase family 1 member C2
chr 10· Steroid synthesis· 12 records - CYP17A1
cytochrome P450 family 17 subfamily A member 1
chr 10· Steroid synthesis· 9 records - AKR1C4Powers
aldo-keto reductase family 1 member C4
chr 10· Steroid synthesis· 8 records - AKR1C1Powers
aldo-keto reductase family 1 member C1
chr 10· Steroid synthesis· 7 records - HSD3B2
hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 2
chr 1· Steroid synthesis· 7 records - SRD5A3
steroid 5 alpha-reductase 3
chr 4· Steroid synthesis· 6 records
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