Cytochrome P450 3As Gene Expression and Testosterone 6.BETA.-Hydroxylase Activity in Human Fetal Membranes and Placenta at Full Term

Abstract

Cytochrome P450 represent a superfamily of heme proteins that play a critical role in the oxidative metabolism of xenobiotics and endogenous substances, and there are several isoforms. The human CYP3A subfamily contains mainly three isoforms, CYP3A4, CYP3A5, and CYP3A7.3)CYP3A4 is a major isoform that accounts for about 30% of the amount of total CYP in human adult livers and is responsible for approximately 50% of the metabolism by CYPs of known drugs in humans. 4,5) CYP3A5 is expressed polymorphically throughout development in the liver.6,7) CYP3A7 is a major CYP isoform in the human fetal and newborn liver. 8)It is known that the human placenta contains multiple CYP isoforms in the mitochondria and endoplasmic reticulum of trophoblastic cells.9) The type and amount of expressed CYPs varies depending on the period of gestation and maternal health status. 10,11) In general, it appears that the placenta expresses a wider variety of CYP isoforms in the first trimester than at term. 12,13) Thus it has been suggested that xenobiotic metabolism in the placenta may be feto-protective during the critical embryogenic and organogenesis stage prior to the second trimester, when it is most susceptible to the effects of teratogens, the expression of CYP mRNAs is maximal.14) However, the central nervous system develops throughout the pregnancy and may also be affected in the later stages of pregnancy. Even though, as described above, various studies of enzymes related to pharmacokinetics in human placenta have been reported, there is only limited research in fetal membranes. The fetal membranes, which extend from the placenta, are an important barrier between the fetus and mother. The membranous structure that surrounds the developing fetus and forms the amniotic cavity is derived from fetal tissue except for decidua and is composed of three layers: amnion (inner layer), chorion leave (middle layer) and decidua (outer layer). The amnion is a translucent structure adjacent to the amniotic fluid. The chorion leave is a more opaque membrane that is attached to the decidua (i.e., maternal tissue that lines the uterus during pregnancy). The amnion and chorion leave are separated by the exocelomic cavity until approximately three months gestation, when they become fused. These membranes regulate the access of substances including drugs and other harmful chemicals to and from the amniotic fluid and, hence, the fetus.15) In recent years, it has been reported that the multidrug resistance/P-glycoprotein gene (MDR1/P-gp) and breast cancer resistance protein (BCRP), belong to the ATP-binding cassette transporter family are expressed in human fetal membranes including decidua. 16,17) It is considered that the role of these transporters is to discharge drugs in amniotic fluid and to keep out transfer of drugs from the maternal side via the uterus. It is well established that P-glycoprotein transports many drugs that are metabolized by CYP3A4 and many modulators of P-glycoprotein also modulate the CYP3A gene family.18) To the best of o...

Comparison of extravillous trophoblast cells derived from human embryonic stem cells and from first trimester human placentas

“…These are opportune targets for further investigation. Similarly, of the 20 genes most down-regulated in both placental/HLA-G + and BMP-hESC/HLA-G + cells, only ERN1 [47], MXD1 [48], CYP3A7 [49], SLC22A11 [50] and CD70 [51] have been previously identified in placenta. Also intriguing was the gene, C8orf47 , which was up-regulated in both placental/HLA-G + and BMP-hESC/HLA-G + .…”

Placental control of drug delivery

“…CYP19A11 is capable of metabolizing glyburide, which exhibits limited transplacental passage. Glyburide can also be metabolized by CYP3A7, which is present in the placenta, but metabolism of glyburide by CYP3A7 has only been studied in the liver [112,113]. Another important xenobiotic, ethanol, is shown to be partially oxidized by CYP2E1 to make acetaldehyde [114].…”

Induction of human cytochrome P450 3A enzymes in cultured placental cells by thalidomide and relevance to bioactivation and toxicity

“…Regarding human fetal specific P450 3A7 in the placenta (Schuetz et al, 1993; Maezawa et al, 2010), mRNA levels of P450 3A7 have not been determined in the placental BeWo cells (Prouillac and Lecoeur, 2010). Because mRNA prepared from adult human livers showed no detectable P450 3A7 mRNA levels, we used the control samples from human fetal livers (Shimada, et al, 1996).…”