XENOBIOTIC-METABOLIZING CYTOCHROME-P450 ENZYMES IN THE HUMAN FETOPLACENTAL UNIT - ROLE IN INTRAUTERINE TOXICITY

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 fetu s, including in utero death, initiation of birth defects, and producti on of functional abnormalities. It is well established that numerous x enobiotics are not necessarily toxic as such, but are enzymatically tr ansformed in the body to reactive and toxic intermediates. The cytochr ome P450 (CYP) enzymes are known to catalyze oxidative metabolism of a vast number of compounds, including many proteratogens, procarcinogen s, and promutagens. About 20 xenobiotic-metabolizing CYP forms are kno wn to exist in humans. Most of these forms are most abundant in the li ver, but examples of exclusively extrahepatic CYP forms also exist. Un like rodents, the liver of the human fetus and even embryo possesses r elatively well-developed metabolism of xenobiotics. There is experimen tal evidence for the presence of CYP1A1, CYP1B1, CYP2C8, CYP2D6, CYP2E 1, CYP3A4, CYP3A5, and CYP3A7 in the fetal liver after the embryonic p hase (after 8 to 9 weeks of gestation). Significant xenobiotic metabol ism occurs also during organogenesis (before 8 weeks of gestation). Al so, some fetal extrahepatic tissues, most notably the adrenal, contain substantial levels of CYP enzymes. The full-term human placenta is de void of many CYP activities present in liver. Placental CYP1A1 is high ly inducible by maternal cigarette smoking. Other forms present in ful l-term placenta include CYPLCB1 and CYP19 (steroid aromatase), which a lso contribute to the oxidation of some xenobiotics. At earlier stages of pregnancy, the placenta may express a wider array of CYP genes, in cluding CYP2C, CYP2D6, and CYP3A7. Due to the small size of the fetus and low abundance of CYPs in placenta, the contribution of fete-placen tal metabolism to overall gestational pharmacokinetics of drugs is pro bably minor. In contrast, several toxic outcomes have been ascribed to altered metabolic patterns in the feto-placental unit, including a pu tative association between reduced placental oxidative capacity and bi rth defects. Examples of human teratogens that are substrates for CYP enzymes include thalidomide, phenytoin, ethanol, and several hormonal agents. Recent studies have improved our understanding of the expressi on and regulation of individual CYP genes in the fetus and placenta, a nd the stage is set for applying this knowledge with mon precision to the role of xenobiotic metabolism in abnormal intrauterine development in humans.