Metabolic Activation of Proestrogens in the Environment by Cytochrome P450 System

Abstract

Liver microsome-mediated activation of proestrogens in the environment is reviewed here. Proestrogens such as methoxychlor, trans-stilbene, diphenyl, diphenylmethane, 2,2-diphenylpropane, benzo[a]pyrene, benzophenone, 2-nitrofluorene (NF), chalcone, trans-4-phenyl-3-buten-2-one and styrene oligomers are negative in in vitro estrogen screening tests. However, those proestrogens exhibit estrogenic activity after metabolic activation by the microsomal cytochrome P450 system. In these cases, hydroxylated derivatives of the compounds are formed as major metabolites, and these metabolites exhibit significant estrogenic activities. Thus, the estrogenic activities of proestrogenic compounds are a consequence of metabolism of the parent compounds. Various candidates for proestrogens among medicines and insecticides are also discussed.

Fate of Estrogenic Compounds during Municipal Sludge Stabilization and Dewatering

“…Addition of an unhindered phenolic OH group in a para position to compounds with molecular weights between 140-250 Daltons is known to increase estrogenic response in the YES bioassay (Miller, 2001). Phenolic hydroxylation of benzophenone and other proestrogens by a common enzymatic catalyst in the cyctochrome P450 system can convert these compounds into estrogenic forms (Kawamura, 2003;Kitamura, 2008).…”

Hydroxylated polychlorinated biphenyls in the environment: sources, fate, and toxicities

“…Besides PCBs, a variety of xenobiotic pollutants are proestrogens, including trans -stilbene, bisphenol A, benzophenone, and methoxychlor. As it is the case with PCBs, proestrogens typically become estrogenic (or more estrogenic) after addition of a hydroxyl group on an aryl core in para of a bulky hydrophobic group (Kitamura et al 2008). …”

Endocrine disrupting potency of organic pollutant mixtures isolated from commercial fish oil evaluated in yeast-based bioassays

“…Competitive binding is a required condition for direct-acting compounds, and their affinity can be measured using ligand-binding assays. Some chemicals act indirectly, showing endocrine disrupting potency only after metabolic activation, i.e., after transformation into a related derivative but more native, structurally similar to hormone [ 8 – 9 ].…”