Placenta mechanism

Recently, Prasad et al. cloned a mammalian Na+-dependent multivitamin transporter (SMVT) from rat placenta [305], This transporter is very highly expressed in intestine and transports pantothenate, biotin, and lipoate [305, 306]. Additionally, it has been suggested that there are other specific transport systems for more water-soluble vitamins. Takanaga et al. [307] demonstrated that nicotinic acid is absorbed by two independent active transport mechanisms from small intestine one is a proton cotransporter and the other an anion antiporter. These nicotinic acid related transporters are capable of taking up monocarboxylic acid-like drugs such as valproic acid, salicylic acid, and penicillins [5], Also, more water-soluble transporters were discovered as Huang and Swann [308] reported the possible occurrence of high-affinity riboflavin transporter(s) on the microvillous membrane. 

The biogenic amines are the preferred substrates of MAO. The enzyme comes in two flavors, MAO-A and MAO-B, both of which, like FMO, rely on the redox properties of FAD for their oxidative machinery. The two isoforms share a sequence homology of approximately 70% (81) and are found in the outer mitochondrial membrane, but they differ in substrate selectivity and tissue distribution. In mammalian tissues MAO-A is located primarily in the placenta, gut, and liver, while MAO-B is predominant in the brain, liver, and platelets. MAO-A is selective for serotonin and norepinephrine and is selectively inhibited by the mechanism-based inhibitor clorgyline (82). MAO-B is selective for /1-phcncthylaminc and tryptamine, and it is selectively inhibited by the mechanism-based inhibitors, deprenyl and pargyline (82) (Fig. 4.32). Recently, both MAO-A (83) and MAO-B (84) were structurally characterized by x-ray crystallography. 

The degree of exposure of the fetus to a particular substance can be best assessed in human subjects, but concerns of fetal safety have restricted the use of this approach. Moreover, clinical studies cannot elucidate the various mechanisms that contribute to transplacental transport of a particular compound. There are many structural differences between the human placenta and the placenta of other mammalian species, which complicates extrapolation of data obtained from in vivo animal models to humans [7], Thus, several ex vivo and in vitro techniques have been developed to study the placental role in drug transfer and metabolism during pregnancy and there are some excellent articles that discuss these systems in detail [7], Both isolated tissues and various cell culture techniques are currently in use and these have been summarized below. 

Primarily to elucidate transporter localization and function, vesicles enriched in trophoblast apical or basolateral membranes have frequently been utilized. To give a few instances, they have been used to investigate P-gp-mediated transport, mechanisms of transport of cationic compounds, drug interactions with nutrient transport, and differences in amino acid transport in pathological conditions of the placenta [36, 40-42], Briefly, for preparation of microvillus membrane vesicles the cord, amniochorion and decidua are removed from placenta, and the tissue cut on the maternal side. The mince is stirred to loosen... 

I.M. Doughty, J.D. Glazier, S.L. Greenwood, R.D. Boyd, and C.P. Sibley. Mechanisms of matemofetal chloride transfer across the human placenta perfused in vitro. Am I Physiol. 27LR1701-R1706 (1996). 

Based on a combination of available human case studies and experiments with laboratory animals, the major public health concerns associated with exposure to 1,4-dichlorobenzene are effects on the liver, kidneys, and blood. Some immunological, dermatological, and neurological effects have also been reported in exposed humans. There is information from animal studies which raises the question of whether 1,4-dichlorobenzene can cross the placenta and elicit structural effects on the developing fetus. Data from a study conducted in rats using the intraperitoneal route have demonstrated sperm abnormalities. Cancer of the liver as a result of lifetime exposure to 1,4-dichlorobenzene has been shown in mice, and renal cancer has been reported in male rats. However, recent studies related to the mechanism of renal carcinogenesis in rats suggest that these tumors may not be expected to occur in exposed humans. Issues relevant to children are explicitly discussed in Section 2.6, Children s Susceptibility, and Section 5.6, Exposures of Children. 

Active efflux transporters also exist in the placenta, analogous to the gut and blood-brain barrier. These are Pgp, multidrug resistance-associated protein (MRP), and breast cancer resistance protein (BCRP). These transport proteins are located in many tissues but also appear to be expressed in the placenta. Though the substrate specificities of these proteins have not been completely described, they appear to function as efflux transporters, moving endogenous and exogenous chemicals from the placental cells back to the systemic circulation. In this way, they serve as a mechanism to protect the fetus from exposure to unintended chemicals. 

If both maternal and embryo-fetal toxicity have ensued, a frequent interpretation is that the maternal toxicity has caused the embryo-fetal toxicity. In the author s view, it is more likely that a dose that is toxic to the adult is going to be toxic to the conceptus, and there is no need to invoke undefined (and probably indefinable) indirect mechanisms. Particularly in the case of small molecules that are lipid-soluble and that can cross the placenta freely, the maternal and fetal systems could be said to constitute a single pharmacokinetic compartment, and the conceptus will be exposed directly to the drug. It would not be surprising if the conceptus manifested effects of toxicity in cases where adult toxicity has been shown. 

While there seems to be little in common between intractable epilepsy and cancer, researchers in each field have focused on a common mechanism underlying multidrug resistance a cellular pump called P-glycoprotein (Pgp). Pgp protects cells from toxic substances by actively excreting the toxic agent. The pumps reside in tissues that are extensively exposed to toxic material liver, lungs, kidney, intestine, placenta, and blood-brain barrier. How-... 

The mechanisms that underlie ethanol s teratogenic effects are unknown. Ethanol rapidly crosses the placenta and reaches concentrations in the fetus that are similar to those in maternal blood. The fetal liver has little or no alcohol dehydrogenase activity, so the fetus must rely on maternal and placental enzymes for elimination of alcohol. 

Two mechanisms help protect the fetus from drugs in the maternal circulation (1) The placenta itself plays a role both as a semipermeable barrier and as a site of metabolism of some drugs passing through it. Several different types of aromatic oxidation reactions (eg, hydroxylation, /V-dealkylation, demethylation) have been shown to occur in placental tissue. Pentobarbital is oxidized in this way. Conversely, it is possible that the metabolic capacity of the placenta may lead to creation of toxic metabolites, and the placenta may therefore augment toxicity (eg, ethanol, benzpyrenes). (2) Drugs that have crossed the placenta enter the fetal circulation via the umbilical vein. 

When the embryo arrives in the uterine cavity, the trophectoderm infiltrates the uterine epithelium by a poorly characterized mechanism. Several maternal and embryonic factors are crucial to implantation. These factors include colony stimulating factor, leukaemia inhibitory factor, interleukin- and several proteolytic enzymes. Before the placenta develops, the implanted embryo is nourished by histotrophic material from degradation of endometrial cells during implantation. The embryo is also nourished by secretions from endometrial glands and by the yolk sac the latter persists for different time periods and plays different roles in different species. 

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