The metabolic activation of pentachlorophenol to chloranil as a potent inhibitor of human and rat placental 3 I3-hydroxysteroid dehydrogenases

Pentachlorophenol (PCP) is a widely used pesticide. However, whether PCP and its metabolite chloranil have endocrine -disrupting effects by inhibiting placental 3 I3 -hydroxysteroid dehydrogenase 1 (3 I3 -HSD1) remains unclear. The study used in vitro assays with human and rat placental microsomes to measure 3 I3 -HSD activity as well as human JAr cells to evaluate progesterone production. The results showed that PCP exhibited moderate inhibition of human 3 I3 -HSD1, with an IC 50 value of 29.83 mu M and displayed mixed inhibition in terms of mode of action. Conversely, chloranil proved to be a potent inhibitor, demonstrating an IC 50 value of 147 nM, and displaying a mixed mode of action. PCP significantly decreased progesterone production by JAr cells at 50 mu M, while chloranil markedly reduced progesterone production at >= 1 mu M. Interestingly, PCP and chloranil moderately inhibited rat placental homolog 3 I3 -HSD4, with IC 50 values of 27.94 and 23.42 mu M, respectively. Dithiothreitol (DTT) alone significantly increased human 3 I3 -HSD1 activity. Chloranil not PCP mediated inhibition of human 3 I3 -HSD1 activity was completely reversed by DTT and that of rat 3 I3 -HSD4 was partially reversed by DTT. Docking analysis revealed that both PCP and chloranil can bind to the catalytic domain of 3 I3 -HSDs. The difference in the amino acid residue Cys83 in human 3 I3 -HSD1 may explain why chloranil is a potent inhibitor through its interaction with the cysteine residue of human 3 I3 -HSD1. In conclusion, PCP is metabolically activated to chloranil as a potent inhibitor of human 3 I3 -HSD1.