The Function of Cytochrome P450 1A1 Enzyme (CYP1A1) and Aryl Hydrocarbon Receptor (AhR) in the Placenta

Lucie      Stejskalova; Petr      Pavek

Abstract

CYP1A1, an enzyme of the cytochrome P450 superfamily, is the most important xenobiotic-metabolizing enzyme of the placenta for which relevant inducible activity has been demonstrated throughout pregnancy. CYP1A1 metabolizes several drugs and compounds widely used in pharmacotherapy or present in diets. At the same time, this enzyme plays a key role in the bioactivation of procarcinogens and proteratogens, such as arylamines and polycyclic aromatic hydrocarbons (PAHs), which bind to placental and foetal DNA as DNA-adducts. The expression of CYP1A1 is transcriptionally up-regulated through the ligand-activated aryl hydrocarbon receptor (AhR). AhR plays an important role as mediator of an adaptive response to xenobiotics, as well as in normal physiology and embryonic development. Several exogenous AhR ligands, such as PAHs, polychlorinated biphenyls and halogenated dioxins, can be found in the constituents of numerous commercial products, including insulators and flame retardants, or as products of combustion processes, including chimney soot, charbroiled foods and cigarette smoke, or as the product of waste incineration. Exposure to these compounds subsequently affects cellular growth and differentiation, homeostasis, level of growth factors, reproduction function and hormonal regulation. Importantly, elevated CYP1A1 activity through activated AhR in placentas of women smokers has been associated with pregnancy complications, such as premature birth, intrauterine growth retardation (IUGR), structural abnormalities, foetal death or placental abruption, risk of low birth weight, low birth length and low head circumference. We summarize the recent findings related to toxicological consequences of AhR activation and CYP1A1 induction in the human placenta during pregnancy.

Keywords: Aryl hydrocarbon receptor, aryl hydrocarbon receptor nuclear translocator, cigarette smoke, cytochrome P450, CYP1A1, placenta, pregnancy, DNA-adducts, intrauterine growth retardation, AhR activation, Barrier, Biotransformation