Biomedical subjects

Susan Lo

Publications and source records attributed to Susan Lo.

3 recordsLinked to original sources

PubMed2006

Effects of various pesticides on human 5alpha-reductase activity in prostate and LNCaP cells.

Certain pesticides are able to disturb the sex steroid hormone system and to act as antiandrogens. While the different underlying mechanisms remain unclear, inhibition of 5alpha-reductase, the enzyme which is indispensable for the synthesis of DHT and thus normal masculinization, appears to be one of the sensitive targets for endocrine disruption. We therefore tested several endocrine disrupters with antiandrogenic effects in vivo for their influence on 5alpha-reductase activity in two different test systems: (a) an enzyme assay with human Lymph Node Carcinoma of Prostate (LNCaP) cells and (b) an enzyme assay with human prostate tissue homogenate. The selected pesticides and industrial compounds were monobutyltin (MBT), dibutyltin (DBT), tributyltin (TBT), triphenyltin (TPT), diuron, fenarimol, linuron, p,p'DDE, prochloraz and vinclozolin. The synthetic androgen methyltestosterone and the synthetic antiandrogen flutamide, as well as the 5alpha-reductase inhibitor finasteride served as control compounds. The effect of the organotin compounds DBT, TBT and TPT on enzyme activity was approximately the same in both test systems, with IC(50) values ranging between 2.7 and 11.2 microM, while in prostate tissue, methyltestosterone and prochloraz proved to be stronger inhibitors (IC(50) values of 1.9 and 12.4 microM) than in LNCaP cells (IC(50) values of 13.2 and 53.2 microM). The inhibitory impact of finasteride was approximately 130 times stronger in prostate tissue than in LNCaP cells. Fenarimol, flutamide, linuron and p,p'DDE inhibited 5alpha-reductase activity only at very high concentrations (IC(50)> or =24 microM) in prostate homogenates, and not at all in LNCaP cells. On average, the IC(20) values were 3.5 times lower than the IC(50) values. Diuron, MBT and vinclozolin exerted no effect in either of the test systems. The finding of pesticides acting as 5alpha-reductase inhibitors might be of clinical relevance. As a screening tool for putative ED, the tissue assay is the more practical and sensitive method. However, the cell assay can, to some extent, reflect particular cell processes since the living cell is able to compensate moderate toxicological effects of the ED on cell viability, and possibly also their impact on 5alpha-reductase activity.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

PubMed2006

COMPRENDO: Focus and approach.

Tens of thousands of man-made chemicals are in regular use and discharged into the environment. Many of them are known to interfere with the hormonal systems in humans and wildlife. Given the complexity of endocrine systems, there are many ways in which endocrine-disrupting chemicals (EDCs) can affect the body's signaling system, and this makes unraveling the mechanisms of action of these chemicals difficult. A major concern is that some of these EDCs appear to be biologically active at extremely low concentrations. There is growing evidence to indicate that the guiding principle of traditional toxicology that "the dose makes the poison" may not always be the case because some EDCs do not induce the classical dose-response relationships. The European Union project COMPRENDO (Comparative Research on Endocrine Disrupters--Phylogenetic Approach and Common Principles focussing on Androgenic/Antiandrogenic Compounds) therefore aims to develop an understanding of potential health problems posed by androgenic and antiandrogenic compounds (AACs) to wildlife and humans by focusing on the commonalities and differences in responses to AACs across the animal kingdom (from invertebrates to vertebrates) .

Androgens↗

PubMed2003

Dithioerythritol (DTE) prevents inhibitory effects of triphenyltin (TPT) on the key enzymes of the human sex steroid hormone metabolism.

Organotins are known to induce imposex (pseudohermaphroditism) in marine neogastropods and are suggested to act as specific endocrine disruptors, inhibiting the enzyme-mediated conversion of steroid hormones. Therefore, we investigated the in vitro effects of triphenyltin (TPT) on human 5alpha-reductase type 2 (5alpha-Re 2), cytochrome P450 aromatase (P450arom), 17beta-hydroxysteroid dehydrogenase type 3 (17beta-HSD 3), 3beta-HSD type 2 and 17beta-HSD type 1 activity. First, the present study demonstrates that significant amounts of TPT occurred in the blood of eight human volunteers (0.17-0.67 microg organotin cation/l, i.e. 0.49-1.92 nmolcation/l). Second, TPT showed variable inhibitory effects on all the enzymes investigated. The mean IC(50) values were 0.95 microM for 5alpha-Re 2 (mean of n=4 experiments), 1.5 microM for P450arom (n=5), 4.0 microM for 3beta-HSD 2 (n=1), 4.2 microM for 17beta-HSD 3 (n=3) and 10.5 microM for 17beta-HSD 1 (n=3). To exclude the possibility that the impacts of TPT are mediated by oxidizing essential thiol residues of the enzymes, the putative compensatory effects of the reducing agent dithioerythritol (DTE) were investigated. Co-incubation with DTE (n=3) resulted in dose-response prevention of the inhibitory effects of 100 microM deleterious TPT concentrations on 17beta-HSD 3 (EC(50) value of 12.9 mM; mean of n=3 experiments), 3beta-HSD 2 (0.90 mM; n=3), P450 arom (0.91 mM; n=3) and 17beta-HSD 1 (0.21 mM; n=3) activity. With these enzymes, the use of 10mM DTE resulted in an at least 80% antagonistic effect, whereas, the effect of TPT on 5alpha-Re 2 was not compensated. In conclusion, the present study shows that TPT acts as an unspecific, but significant inhibitor of human sex steroid hormone metabolism and suggests that the inhibitory effects are mediated by the interaction of TPT with critical cysteine residues of the enzymes.

17-Hydroxysteroid Dehydrogenases↗