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

Abstract

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 5α-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 5α-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 5α-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 μM, while in prostate tissue, methyltestosterone and prochloraz proved to be stronger inhibitors (IC 50 values of 1.9 and 12.4 μM) than in LNCaP cells (IC 50 values of 13.2 and 53.2 μM). 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 5α-reductase activity only at very high concentrations (IC 50 ⩾ 24 μM) 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 5α-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 5α-reductase activity.