SummaryShort-chain dehydrogenases/reductases (SDR) constitute one of the largest enzyme superfamilies with presently over 46 000 members. In phylogenetic comparisons, members of this superfamily Correspondence to: Bengt Persson and Udo Oppermann, bpn@ifm.liu.se, udo.oppermann@sgc.ox.ac.uk. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. show early divergence where the majority have only low pair-wise sequence identity, although sharing common structural properties. The SDR enzymes are present in virtually all genomes investigated, and in humans over 70 SDR genes have been identified. In humans, these enzymes are involved in the metabolism of a large variety of compounds, including steroid hormones, prostaglandins, retinoids, lipids and xenobiotics. It is now clear that SDRs represent one of the oldest protein families and contribute to essential functions and interactions of all forms of life. As this field continues to grow rapidly, a systematic nomenclature is essential for future annotation and reference purposes. A functional subdivision of the SDR superfamily into at least 200 SDR families based upon hidden Markov models forms a suitable foundation for such a nomenclature system, which we present in this paper using human SDRs as examples. NIH Public Access

Abstract-Although it is well known that estrogenic steroidal hormones are able to affect the sexual development and reproduction of fish at low concentrations, no data on environmental effects of the class of progestogenic hormones are available yet. Synthetic gestagens (progestins) are a component in oral contraceptives. Upon their use, a fraction of the progestins will be excreted via urine into the aquatic environment. On the basis of their pharmacological action in mammals, it is supposed that fish reproduction is the most sensitive endpoint for the progestin treatment. In order to test this assumption, the effects of two progestins currently marketed in contraceptive formulations, levonorgestrel (LNG) and drospirenone (DRSP), were investigated in adult fathead minnows (Pimephales promelas) following an Organization for Economic Cooperation and Development 21-d fish reproduction screening assay draft protocol with additional end points. Levonorgestrel was tested at measured concentrations of 0.8, 3.3, and 29.6 ng/L, and DRSP at concentrations of 0.66, 6.5, and 70 mg/L. Both tested progestins caused an inhibition of reproduction. For LNG, this occurred at concentrations of $0.8 ng/L, no no-observed-effect concentration (NOEC) could be defined. Higher concentrations resulted in masculinization of females with de novo synthesis of nuptial tubercles. Drospirenone treatment, however, affected the reproductive success of fathead minnow at concentrations of 6.5 mg/L and higher with a clear dose-response relationship and a NOEC of 0.66 mg/L, which is above environmentally relevant concentrations.

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ABSTRACT:A first step in the enzymatic disposition of the antineoplastic drug doxorubicin (DOX) is the reduction to doxorubicinol (DOX-OL). Because DOX-OL is less antineoplastic but more cardiotoxic than the parent compound, the individual rate of this reaction may affect the antitumor effect and the risk of DOX-induced heart failure. Using purified enzymes and human tissues we determined enzymes generating DOX-OL and interindividual differences in their activities. Human tissues express at least two DOX-reducing enzymes. High-clearance organs (kidney, liver, and the gastrointestinal tract) express an enzyme with an apparent K m of ϳ140 M. Of six enzymes found to reduce DOX, K m values in this range are exhibited by carbonyl reductase 1 (CBR1) and aldo-keto reductase (AKR) 1C3. CBR1 is expressed in these three organs at higher levels than AKR1C3, whereas AKR1C3 has higher catalytic efficiency. However, inhibition constants for DOX reduction with 4-amino-1-tert-butyl-3-(2-hydroxyphenyl)pyrazolo[3,4-d]pyrimidine(an inhibitor that can discriminate between CBR1 and AKR1C3) were identical for CBR1 and human liver cytosol, but not for AKR1C3. These results suggest that CBR1 is a predominant hepatic DOX reductase. In cytosols from 80 human livers, the expression level of CBR1 and the activity of DOX reduction varied >70-and 22-fold, respectively, but showed no association with CBR1 gene variants found in these samples. Instead, the interindividual differences in CBR1 expression and activity may be mediated by environmental factors acting via recently identified xenobiotic response elements in the CBR1 promoter. The variability in the CBR1 expression may affect outcomes of therapies with DOX, as well as with other CBR1 substrates.

Carbonyl reduction of aldehydes, ketones, and quinones to their corresponding hydroxy derivatives plays an important role in the phase I metabolism of many endogenous (biogenic aldehydes, steroids, prostaglandins, reactive lipid peroxidation products) and xenobiotic (pharmacologic drugs, carcinogens, toxicants) compounds. Carbonyl-reducing enzymes are grouped into two large protein superfamilies: the aldo-keto reductases (AKR) and the short-chain dehydrogenases/reductases (SDR). Whereas aldehyde reductase and aldose reductase are AKRs, several forms of carbonyl reductase belong to the SDRs. In addition, there exist a variety of pluripotent hydroxysteroid dehydrogenases (HSDs) of both superfamilies that specifically catalyze the oxidoreduction at different positions of the steroid nucleus and also catalyze, rather nonspecifically, the reductive metabolism of a great number of nonsteroidal carbonyl compounds. The present review summarizes recent findings on carbonyl reductases and pluripotent HSDs of the SDR protein superfamily.