Quantum chemical simulations revealed the toxicokinetic mechanisms of organic phosphorus flame retardants catalyzed by P450 enzymes.

The metabolic fate and toxicokinetics of organic phosphorus flame retardants catalyzed by cytochrome P450 enzymes (CYPs) are here investigated by in silico simulations, leveraging an active center model to mimic the CYPs, triphenyl phosphate (TPHP), tris(2-butoxyethyl) phosphate and tris(1,3-dichloro-2-propyl) phosphate as substrates. Our calculations elucidated key main pathways and predicted products, which were corroborated by current in vitro data. Results showed that alkyl OPFRs are eliminated faster than aryl and halogenated alkyl-substituted OPFRs. In addition, we discovered a proton shuttle pathway for aryl hydroxylation of TPHP and P = O bond-assisted H-transfer mechanisms (rather than nonenzymatic hydrolysis) that lead to O-dealkylation/dearylation of phosphotriesters.

Study of 202 natural, synthetic, and environmental chemicals for binding to the androgen receptor.

A number of environmental and industrial chemicals are reported to possess androgenic or antiandrogenic activities. These androgenic endocrine disrupting chemicals may disrupt the endocrine system of humans and wildlife by mimicking or antagonizing the functions of natural hormones. The present study developed a low cost recombinant androgen receptor (AR) competitive binding assay that uses no animals. We validated the assay by comparing the protocols and results from other similar assays, such as the binding assay using prostate cytosol. We tested 202 natural, synthetic, and environmental chemicals that encompass a broad range of structural classes, including steroids, diethylstilbestrol and related chemicals, antiestrogens, flutamide derivatives, bisphenol A derivatives, alkylphenols, parabens, alkyloxyphenols, phthalates, siloxanes, phytoestrogens, DDTs, PCBs, pesticides, organophosphate insecticides, and other chemicals. Some of these chemicals are environmentally persistent and/or commercially important, but their AR binding affinities have not been previously reported. To the best of our knowledge, these results represent the largest and most diverse data set publicly available for chemical binding to the AR. Through a careful structure-activity relationship (SAR) examination of the data set in conjunction with knowledge of the recently reported ligand-AR crystal structures, we are able to define the general structural requirements for chemical binding to AR. Hydrophobic interactions are important for AR binding. The interaction between ligand and AR at the 3- and 17-positions of testosterone and R1881 found in other chemical classes are discussed in depth. The SAR studies of ligand binding characteristics for AR are compared to our previously reported results for estrogen receptor binding.