Estradiol 17beta-dehydrogenase Type 2

Synonyms: 17bHSD2, HSD17B2, 17b-HSD2, 17ß-HSD2, 17beta-HSOR Type 2, 17b-HSOR II

EC Number: EC (It's important to note that EC does not distinguish between Type 1, Type 2, etc. It includes all subtypes.)

Estradiol 17beta-dehydrogenase Type 2 (17bHSD2) performs oxidation, not reduction, catalyzing the conversion of estradiol onto estrone in humans using NAD+ as a cofactor. Type 1 performs the opposite action reducing estrone into estradiol. This article is specific to Type 2.

17bHSD2 appears to be most active in the small intestines. In one study 17bHSD2 activity was detected in the stomach, duodenum, ileum, colon and rectum. 17bHSD2 mRNA was found to be most abundant in the small intestine. 17bHSD2 immunoreactivity was localized almost exclusively to the absorptive epithelium, which may be involved in the inactivation of excessive endogenous and exogenous active sex steroids. Results from the study suggested that the human gastrointestinal tract is an important sex steroid metabolizing organ in humans.[7]

Dehydrogenation Reactions

17bHSD2 dehydrogenates estradiol at the 17beta-hydroxy position (along with cofactors NAD+ and NADP+) into estrone (along with NADH, NADPH, and H+).

The cytochrome P450 enzymes CYP2C8, CYP2C9, and CYP2C19 are also able to dehydrogenate estradiol creating estrone.[1]

In this example 17bHSD2 converts estradiol into estrone. It uses NAD+ as a cofactor and produces NADH and H+ as byproducts. Note that this enzyme can also perform the opposite action. It is bidirectional.

Substrate 17bHSD2 End Product
Estradiol Estrone
Estradiol.png Estrone.png
Cofactor Byproducts
NAD.png H+ NADH.png

This enzyme also catalyzes the conversion of the alcohol 1'-hydroxyestragole (a metabolite of the allylbenzene methyl chavicol) to the phenyl vinyl ketone 1'-oxoestragole, a reaction not catalyzed by cytochrome P450 enzymes. This reaction requires NAD+ (Nicotinamide adenine dinucleotide) as a cofactor.[11] It produces NADH and H+ as byproducts.

Substrate 17bHSD2 End Product
1'-hydroxyestragole 1'-Oxoestragole
1-hydroxyestragole.png 1-Oxoestragole.png
Cofactor Byproducts
NAD.png H+ NADH.png

Inhibitors and Inducers

Potent Inhibitors Strength Dosage Verified in Humans
Quercetin (in tea, apples, onions) 50% inhibition IC50 = 1.5 µM[10][11] ?
Vegetable oils1 ? ? ?
Linoleic acid[15] 58% inhibition 0.018 mM ?
Linolenic acid[15] 34% inhibition 0.018 mM ?
Naringenin (in grapefruit) 50% inhibition IC50 = 14.4 µM[10] ?
Oleic acid[15] 100% inhibition 0.018 mM ?
Inhibitors Strength Dosage Verified in Humans
Kaempferol [11][12] ? ? ?
Kaempferide [11][12] ? ? ?
Galangin [11][12] ? ? ?
Inducers Strength Dosage Verified in Humans
5α-dihydrotestosterone[14] ? ? ?
All-trans retinoic acid (tretinoin) 5-10 fold increase[8][13] 10-6 M ?
Androgen[14] ? ? ?
Calcitriol[14] ? ? ?
9-Cis-retinoic acid (alitretinoin) 5-10 fold increase[8][13] 10-6 M ?
Gallic acid 30% induction[5] ? ?
Genistein (in Kudzu) [9] 19.5% induction 100 nM ?
Genistein (in Kudzu) [9] 77% induction ? ?
Palm oil carotenoids[16] "significant stimulation" 0.001 mM ?
Vitamin D3[2] ? ? ?

1. Role of cytochrome P450 in estradiol metabolism in vitro.
Cheng ZN, Shu Y, Liu ZQ, Wang LS, Ou-Yang DS, Zhou HH.; PubMed PMID: 11741520 (Download Attached PDF Document)
Estrogen metabolism in human colorectal cancer cells. Fiorelli G, Picariello L, Martineti V, Tognarini I, Tonelli F, Brandi ML.; PubChem PMID 12163140
3. Flavonoids and cinnamic acid derivatives as inhibitors of 17beta-hydroxysteroid dehydrogenase type 1.
Brozic P, Kocbek P, Sova M, Kristl J, Martens S, Adamski J, Gobec S, Lanisnik Rizner T. PubChem PMID 18835421
Cinnamic acids as new inhibitors of 17beta-hydroxysteroid dehydrogenase type 5 (AKR1C3). Brozic P, Golob B, Gomboc N, Rizner TL, Gobec S.; PubChem PMID 16337332
5. Olive oil phenols inhibit human hepatic microsomal activity.
Stupans I, Stretch G, Hayball P. PubChem PMID 10958837
6. Evaluation of human interindividual variation in bioactivation of estragole using physiologically based biokinetic modeling.
Punt A, Jeurissen SM, Boersma MG, Delatour T, Scholz G, Schilter B, van Bladeren PJ, Rietjens IM. PubMed: 19920071
7. 17 beta-Hydroxysteroid dehydrogenase type 2 expression and enzyme activity in the human gastrointestinal tract.
Sano T, Hirasawa G, Takeyama J, Darnel AD, Suzuki T, Moriya T, Kato K, Sekine H, Ohara S, Shimosegawa T, Nakamura J, Yoshihama M, Harada N, Sasano H. PubMed: 11672453
8. Regulation of 17-beta hydroxysteroid dehydrogenase type 2 in human placental endothelial cells.
Su EJ, Cheng YH, Chatterton RT, Lin ZH, Yin P, Reierstad S, Innes J, Bulun SE. PubMed: 17538076
9. Effects of phytoestrogens and synthetic combinatorial libraries on aromatase, estrogen biosynthesis, and metabolism.
Brueggemeier RW, Gu X, Mobley JA, Joomprabutra S, Bhat AS, Whetstone JL. PubMed: 11795395 (Download Attached PDF Document)
10. Discovery of nonsteroidal 17beta-hydroxysteroid dehydrogenase 1 inhibitors by pharmacophore-based screening of virtual compound libraries.
Schuster D, Nashev LG, Kirchmair J, Laggner C, Wolber G, Langer T, Odermatt A. PubMed: 18533708
11. Evaluation of human interindividual variation in bioactivation of estragole using physiologically based biokinetic modeling.
Punt A, Jeurissen SM, Boersma MG, Delatour T, Scholz G, Schilter B, van Bladeren PJ, Rietjens IM. PubMed: 19920071
11. Synthesis, Reactivity and Biological Activity of 17ß-HSD1 Inhibitors Based on a Thieno[2,3-d]pyrimidin-4(3H)-one Core
Annamaria Lilienkampf, Helsinki 2007, ISBN 978-952-10-4211-9
12. Inhibition of 17beta-hydroxysteroid oxidoreductase by flavonoids in breast and prostate cancer cells.
Mäkelä S, Poutanen M, Kostian ML, Lehtimäki N, Strauss L, Santti R, Vihko R. PubMed: 9492340
13. Retinoic acid (RA) regulates 17beta-hydroxysteroid dehydrogenase type 2 expression in endometrium: interaction of RA receptors with specificity protein (SP) 1/SP3 for estradiol metabolism.
J Clin Endocrinol Metab. 2008 May;93(5):1915-23. doi: 10.1210/jc.2007-1536. Epub 2008 Feb 12.; Cheng YH, Yin P, Xue Q, Yilmaz B, Dawson MI, Bulun SE.; PMID: 18270252
14. Vitamin D, Lipid Metabolism and Prostate Cancer
Volume 1380 of Acta Universitatis Tamperensis; Wang Jing-Huan; Tampere University Press, 2009; ISBN 9514475828, 9789514475825
15. Inhibitors of 17 beta-hydroxysteroid dehydrogenases.
Poirier D.; Curr Med Chem. 2003 Mar;10(6):453-77.; PMID: 12570693
16. Effect of retinoic acid and palm oil carotenoids on oestrone sulphatase and oestradiol-17beta
Ng JH, Nesaretnam K, Reimann K, Lai LC.; Int J Cancer. 2000 Oct 1;88(1):135-8.; hydroxysteroid dehydrogenase activities in MCF-7 and MDA-MB-231 breast cancer cell lines.; PMID: 10962451
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