Biotransformation of Endocrine Disrupting Compounds by Selected Phase I and Phase II Enzymes – Formation of Estrogenic and Chemically Reactive Metabolites by Cytochromes P450 and Sulfotransferases

Abstract

The endocrine system is a major communication system in the body and is involved in maintenance of the reproductive system, fetal development, growth, maturation, energy production, and metabolism,. The endocrine system responds to the needs of an organism by secreting a wide variety of hormones that enable the body to maintain homeostasis, to respond to external stimuli, and to follow various developmental programs. This occurs through complex signalling cascades,with multiple sites at which the signals can be regulated. Endocrine disrupting compounds (EDCs) affect the endocrine system by simulating the action of the naturally produced hormones, by inhibiting the action of natural hormones, by changing the function and synthesis of hormone receptors, or by altering the synthesis, transport, metabolism, and elimination of hormones. It has been established that exposure to environmental EDCs is a risk factor for disruption of reproductive development and oncogenesis in both humans and wildlife. For accurate risk assessment of EDCs, the possibility of bioactivation through biotransformation processes needs to be included since neglecting these mechanisms may lead to undervaluation of adverse effects on human health caused by EDCs and/or their metabolites. This accurate risk assessment should include: (1) possibility of EDCs to be bioactivated into metabolites with enhanced endocrine disruption (ED) effects, and (2) possibility of EDCs to be biotransformed into reactive metabolites that may cause DNA damage. Here, we present an overview of different metabolic enzymes that are involved in the biotransformation of EDCs. In addition, we describe how biotransformation by Cytochromes P450 (CYPs), human estrogen sulfotransferase 1E1 (SULT1E1) and selected other phase II enzymes, can lead to the formation of bioactive metabolites. This review mainly focuses on CYP- and SULT-mediated bioactivation of estrogenic EDCs and summarizes our views on this topic while also showing the importance of including bioactivation and biotransformation processes for improved risk assessment strategies.

Molecular Mechanism of Alternative P450-Catalyzed Metabolism of Environmental Phenolic Endocrine-Disrupting Chemicals

“…Note that dispersion effects lower the H-abstraction barriers by a substantial 2.5 kcal/mol, a magnitude consistent with previous findings for P450 reactions. 67 Another possible reaction path starting from 4,2 RC is the addition of the oxo group of Cpd I onto the unsubstituted aromatic ring of BPA via C-O bond-forming transition states 4,2 TSO, which produce tetrahedral intermediates. As shown in Figure 1, compared with the LS species, TSO in the HS state is more advanced (shorter O…C bond) with a higher degree of aromatic activation.…”

“…3,4 Accurate risk assessment of EDCs requires consideration of bioactivation via biotransformation processes, especially by human cytochrome P450 enzymes (P450), since neglecting these metabolic pathways may lead to undervaluation of their adverse effects on human health, although the metabolism of phenolic chemicals by P450 is minor compared with the glucuronidation pathway under normal circumstances. 3,4 P450 enzymes are a superfamily of monooxygenases distributed through all kingdoms of life, and are responsible for most phase-I biotransformation reactions. [5][6][7][8][9] Some of these conversions produce metabolites that are much more toxic than their parent compounds, an important example being phenolic EDCs.…”

In Silico Prediction of Human Sulfotransferase 1E1 Activity Guided by Pharmacophores from Molecular Dynamics Simulations

“…As a consequence, sulfonation of drugs enforce their inactivation and thus reduces their efficacy (8,9). However, sulfonation can also lead to the formation of chemically reactive or toxic metabolites (10,11). It is now a commonly accepted concept that in some sulfonation reactions with certain molecules, e.g.…”

“…alkylated polycyclic aromatic hydrocarbons or aromatic amines, the resulting sulfate group is electron withdrawing and becomes a good leaving group. Cleavage of this group is further facilitated by resonance and results in highly reactive electrophiles that cause DNA damage (10,11).…”

Incorporation of a metabolizing system in biodetection assays for endocrine active substances

“…Metabolism is classically divided into phase I (hydroxylation, dealkylation, oxidation or reduction) and phase II (conjugation). Many of these enzymatic reactions are oxidative and catalyzed by the mixed function oxidase activities of the cytochrome P450 (CYP) family of enzymes (Reinen and Vermeulen, 2015). However, the reactions are not necessarily detoxifying; a pro-toxicant can also be converted into one or more toxicants by these reactions.…”