Xenobiotic-metabolizing cytochrome P450 enzymes in the human feto-placental unit: role in intrauterine toxicity

Abstract

Practically all lipid-soluble xenobiotics enter the conceptus through placental transfer. Many xenobiotics, including a number of clinically used drugs, are known to cause unwanted effects in the embryo or fetus, including in utero death, initiation of birth defects, and production of functional abnormalities. It is well established that numerous xenobiotics are not necessarily toxic as such, but are enzymatically transformed in the body to reactive and toxic intermediates. The cytochrome P450 (CYP) enzymes are known to catalyze oxidative metabolism of a vast number of compounds, including many proteratogens, procarcinogens, and promutagens. About 20 xenobiotic-metabolizing CYP forms are known to exist in humans. Most of these forms are most abundant in the liver, but examples of exclusively extrahepatic CYP forms also exist. Unlike rodents, the liver of the human fetus and even embryo possesses relatively well-developed metabolism of xenobiotics. There is experimental evidence for the presence of CYP1A1, CYP1B1, CYP2C8, CYP2D6, CYP2E1, CYP3A4, CYP3A5, and CYP3A7 in the fetal liver after the embryonic phase (after 8 to 9 weeks of gestation). Significant xenobiotic metabolism occurs also during organogenesis (before 8 weeks of gestation). Also, some fetal extrahepatic tissues, most notably the adrenal, contain substantial levels of CYP enzymes. The full-term human placenta is devoid of many CYP activities present in liver. Placental CYP1A1 is highly inducible by maternal cigar…