The expression and regulation of drug metabolism in human placenta.
The human placenta oxidizes several xenobiotics, although the spectrum of substrates and metabolic activities when compared with the liver appears restricted. Maternal cigarette smoking or PCB exposure increase the expression of CYP1A1. This induced activity is able to catalyze the activation of benzo(a)pyrene into DNA-bound adducts, both in vitro and in vivo. Studies with RT-PCR technique have demonstrated that first trimester placentae express at the mRNA level CYP1A1, 1A2, 2C, 2D6, 2E1, 2F1, 3A4, 3A5, 3A7 and 4B1 and at full term CYP1A1, 2E1, 2F1, 3A3/4, 3A5 and 3A7. However, more detailed studies on cDNA probes or with specific antibodies or 'diagnostic' substrates for other than CYP1A1, 2E1 and 3A gene products have yielded negative results. Studies on human placenta and a chorioncarcinoma cell line, JEG 3 cells, boulster the concept that placental CYP1A1 and 1B1 - although their expression is Ah receptor and ARNT mediated - is controlled by distinct mechanisms. Aromatase, CYP19, and cholesterol side-chain cleaving, CYP11B, genes, proteins and activities are catalytically active in human placentae throughout the pregnancy and those parameters do not seem to be affected by maternal cigarette smoking but rather maternal health status. However, the substrate binding pocket of aromatase accepts as its substrate several xenobiotics and is responsible for constitutive xenobiotic biotransformations.Functional placental glutathione S-transferase, N-acetyl transferase and epoxide hydrolase are expressed via one gene each and their function reflects the placenta as an endocrine organ rather than a xenobiotic-metabolizing unit. However, markers for oxidative stress can be detected in decreased glutathione S-transferase activities.Because human placenta has quite well defined metabolic characteristics, and obtaining placental samples will not meet any drastic ethical difficulties, it could be used more intensively as a source of metabolizing enzymes in in vitro studies during the course of a drug development program. The human placenta, or its subcellular organelles, could serve as a real alternative model for an extrahepatic tissue in replacing recombinant expression systems especially if CYP11, 19, 1A1 or potentially 2E1 are target enzymes for potential metabolic interactions.
Pasanen
M
Department of Pharmacology and Toxicology, University of Oulu, Kajaanintie 52 D, SF-90220 Oulu, Finland; National Agency for Medicines, Helsinki, Finland