Title: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
Volume: 22
Issue: 4
Author(s): J. Reinen and N.P.E. Vermeulen
Affiliation:
Keywords:
Bioactivation, biotransformation, Cytochromes P450 (CYPs), endocrine disruption (ED), endocrine disrupting
compounds (EDCs), estrogen receptor α(ERα), reactive intermediates, sulfotransferases (SULTs).
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.
