Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q7LGC8 (HSD)
 3,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rat liver 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase (3 alpha-HSD) inactivates circulating steroid hormones and is involved in polycyclic aromatic hydrocarbon (PAH) carcinogenesis. It is the only HSD of known structure in the aldo-keto reductase (AKR) superfamily and may provide a paradigm for other mammalian HSDs in this family. The structure of the 3 alpha-HSD.NADP+ binary complex has been determined at 2.7 A resolution and refined to a crystallographic R-factor of 23.4% with good geometry. The model is similar to other binary complexes in the AKR superfamily in that NADP+ binds at the C-terminal end of an alpha/beta barrel. However, it is unique in that NADP+ is bound in two alternate conformations, probably because of the lack of a salt-linked "safety belt" over the pyrophosphate bridge. The structure supports a previously proposed catalytic mechanism for carbonyl reduction in which Tyr 55 is the general acid, and its effective pKa is lowered by the adjacent Lys 84. We present evidence that the structurally distinct short-chain dehydrogenase/reductase (SDR) superfamily may have convergently evolved a similar catalytic mechanism. Insight into substrate binding is offered by a crystal packing contact in which a neighboring molecule inserts a tryptophan residue (Trp 227) into an apolar cleft in 3 alpha-HSD. This cleft is proximal to the bound NADP+ cofactor and contains a surface of apolar residues (Leu 54, Trp 86, Leu 122, Phe 128, Phe 129, Leu 137, Phe 139), making it a likely candidate for the substrate-binding site. Thus, in forming this crystal contact, Trp 227 may mimic a portion of a bound steroid. In addition, we propose that a water molecule in the active site indicates the position of the hydroxyl oxygen in a 3 alpha-hydroxysteroid substrate. Knowledge of the position of this water molecule, combined with the stereochemistry of hydride transfer, suggests that the alpha face of a bound steroid will be oriented toward the side of the apolar cleft containing Trp 86.
 ...
PMID:Structure of 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase complexed with NADP+. 871 59

Naturally occurring chlorophylls (Chl) have shown anti-mutagenic activity but little is known about their chemoprotective properties in vivo. This study examined the effect of Chl on formation in vivo of DNA adducts by the potent environmental carcinogen dibenzo[a,l]pyrene (DBP), using rainbow trout as the animal model. Fingerling trout were fed diets containing 200 p.p.m. DBP alone or with one of the following preparations incorporated at 3000 p.p.m. total chlorins: purified pheophytin a (Phe a) (94%); semi-purified Chl a (77%, 23% Phe a), commercial Chl a (88%, 12% other Chl a-related compounds); crude spinach extract (53% Chl a, 19% Chl b, 14% Phe a, 9% carotenoids); commercial Cu-chlorophyllin (55% chlorins, 45% neutral salts), as a known inhibitory control. After 2 weeks dietary treatment, the animals were killed and organs were collected. Stable DBP-DNA adducts from liver were quantified after 33P-post-labeling and separation by reversed-phase HPLC. Total DBP-DNA adducts in the DBP-only group were 2.46 +/- 0.32 adducts/10(6) nucleotides. All chlorophyll treatment groups showed significantly lower adduct levels (P < 0.001, Tukey's HSD test), as follows: crude spinach extract, 0.64 +/- 0.14; semi-pure Chl a, 0.5 +/- 0.11; commercial Chl a, 1.26 +/- 0.17; Phe a, 0.95 +/- 0.01; chlorophyllin, 0.78 +/- 0.09. The various treatments suppressed DBP-DNA adducts essentially uniformly across the HPLC profile, which is consistent with complex formation and reduced carcinogen uptake as the predominant protective mechanism. The chlorophyll-mediated reduction in DBP-DNA adducts in vivo is the first demonstration of anti-genotoxic activity of these common dietary phytochemicals in any vertebrate animal model.
Carcinogenesis 1998 Jul
PMID:Chemoprotection by natural chlorophylls in vivo: inhibition of dibenzo[a,l]pyrene-DNA adducts in rainbow trout liver. 968 96

17 beta-hydroxysteroid dehydrogenases (17 beta-HSDs) are involved in the interconversion of biologically active and inactive sex steroids and are considered to play important roles in the in situ metabolism of estrogen in various estrogen dependent tissues. 17 beta-HSD type 1 catalyzes primarily the reduction of estrone (E1) to estradiol (E2), whereas 17 beta-HSD type 2 catalyzes primarily the oxidation of E2 to E1. However, the possible biological roles of these estrogen metabolizing isozymes in human breast cancer, especially in carcinogenesis of the human breast, have not been examined in detail. Because of the potential roles of estrogens in the early stages of human breast carcinogenesis, we have examined the immunolocalization of 17 beta-HSD type 1 and type 2 isozymes and estrogen receptor alpha(ER alpha) in both normal human breast tissue and in breast cancers, including ductal carcinoma in situ (DCIS), proliferative disease without atypia (PDWA) or fibrocystic disease and atypical ductal hyperplasia (ADH). We also correlated these findings with clinicopathological findings, Ki67 antigen, progesterone receptor (PR), c-erbB-2, and p53. 17 beta-HSD type 2 immunoreactivity was sporadically detected in non-proliferative or Ki67 negative ductal epithelia of normal breast, but rarely in breast carcinoma cells. 17 beta-HSD type 1 immunoreactivity was detected in 12/22 (54.5%) PDWA cases, 8/26 (30.8%) ADH cases, and 25/40 (62.5%) DCIS cases, respectively. 17 beta-HSD type 1 immunoreactivity was not statistically correlated with the age of the patients, Ki67 labeling index (LI), and PR LI, p-53 and c-erbB-2 immunoreactivity. There was no significant correlation between ER alpha LI and 17 beta-HSD type 1 immunoreactivity. There was a positive correlation between ER alpha and Ki67 LI in PDWA, whereas a negative correlation was detected between ER alpha and Ki67 LI in DCIS. There was no correlation between ER alpha and Ki67 LI in ADH. These results suggest that in human breast epithelial cells, development of ADH and DCIS may be associated with the loss and/or deviation of oestrogen dependent regulation of cell proliferation.
 ...
PMID:17 beta-Hydroxysteroid dehydrogenase type 1 and type 2 in ductal carcinoma in situ and intraductal proliferative lesions of the human breast. 1081 Apr 3

We determined the ability of human epithelial cervical cells, human cervical microsomes and cytosol to metabolize 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). All preparations metabolized NNK by alpha-hydroxylation, demonstrated by the presence of 4-oxo-4-(3-pyridyl)butyric acid (keto acid), and by carbonyl reduction, illustrated by the formation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). Cervical cells metabolized NNK by the oxidative pathway to an extent comparable to that by the reductive pathway. In both human cervical cytosol and microsomes, the concentration of alpha-hydroxylation products ranged from undetectable to 10 times lower than those of NNAL. An apparent K(m) and V(max) of 7075 microM and 650 pmol/mg/min, respectively, were determined for the keto acid in one microsomal preparation. NNAL was formed in all preparations at the highest levels, ranging from 16.9 to 35.5 pmol/10(6) cells in incubations with ectocervical cells and 6.2 pmol/10(6) cells in incubations with endocervical cells. NNAL levels were 1.88-4.95 and 1.44-2.08 pmol/mg/min in human cervical microsomes and cytosolic fractions, respectively. An apparent K(m) of 739 microM and a V(max) of 1395 pmol/mg/min for NNAL formation were established in the same microsomal preparation used for the keto acid kinetics study. The stereochemistry of the NNAL formed in incubations of NNK with human cervical cells and subcellular fractions was determined by derivatization with (S)-(-)-methylbenzyl isocyanate. Human cervical cells and microsomes both formed the (R)-enantiomer of NNAL almost exclusively; incubations with human cervical cytosol resulted predominantly in the formation of the (S)-enantiomer. Substrates for 11 beta-hydroxysteroid dehydrogenase, cortisone, glycyrrhizic acid and metyrapone all inhibited the formation of NNAL in incubations with human cervical microsomes; the inhibition ranged from 16% to 80%. These studies illustrate that human cervical tissue can metabolize NNK by both oxidative and reductive pathways and that 11 beta-HSD may, in part, be responsible for the carbonyl reduction of NNK.
Carcinogenesis 2001 Jan
PMID:Human cervical tissue metabolizes the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, via alpha-hydroxylation and carbonyl reduction pathways. 1115 48

Aflatoxin B1 (AFB1) is a fungal toxin and contaminant that has been implicated in human liver carcinogenesis. In this study we evaluated the effect of a 65% of total calories from sucrose diet (HSD) for 90 days on hepatic cytochrome P450 (CYP450) and glutathione-S-transferase (GST) activity compared to rats maintained on standard lab chow (0% sucrose). There was a statistically significant increase in the number of S. typhimurium His+ revertants (p < 0.001) generated from the incubation of AFB1 with hepatic microsomes from rats fed a HSD. The HSD did not affect the total microsomal CYP450 content nor content of CYP450 1A2, 2B1, 2 isoforms which activate AFB1. Alkoxyresorufin O-dealkylase activity (MROD, PROD) of microsomes from animals fed HSD was decreased by 73% and 49%, respectively. MROD activity is linked to CYP 1A2 activity while PROD is linked to CYP 2B1,2 activity. Although the amount of CYP 3A was significantly decreased in rats fed a HSD, its activity, determined by the presence of the fluorometric metabolite 7-hydroxyquinidine, was unchanged. GST activity was significantly lower in the rats fed HSD.
 ...
PMID:Effect of high sucrose diet on liver enzyme content and activity and aflatoxin B1-induced mutagenesis. 1279 88