Placental transport mechanisms

Passive diffusion is considered to be the major pathway by which xenobiotics cross the placenta. Paracellular diffusion was shown to be the predominant pathway for transfer of hydrophilic solutes, such as chloride ions across perfused placental lobes and opioid peptides and dextrans across BeWo cells [11-13], It has been proposed that denudations in the syncytiotrophoblasts-containing fibrinoid deposits provide a possible paracellular route across the placenta [14], Transtrophoblast channels in the syncytiotrophoblasts could also be responsible for this mode of diffusion [15], For more lipophilic solutes, the transplacental route appears to be the preferred mode of passage 

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Transendothelial IgG transport may be mediated by binding of endogenous IgG or exogenously administered monoclonal antibodies to FcyRIIa,b on endothelium (e.g., FcyRIIa on skin microvessels [27]) FcyRIIb on placenta villous (fetal) endothelium [28,29] or FcRn on placental syncytiotrophoblasts and fetal endothelium [28], Transcellular transport is further described below under FcRn-mediated transport, I cyRIIa-mediated transport, and specialized skin microvessel transport mechanisms. 

An active transport mechanism has long been suspected to account for the placental barrier that causes maternal and fetal concentrations for many drugs to differ (96 97). Studies of maternal-fetal transport of medications used during pregnancy in HIV-positive women have shown variable penetration into the fetus (98 99). Whereas the maternal-fetal drug ratios for zidovudine lamivudine/ and nevirapine (approximately 0.85 1.0/ and 0.9/ respectively) demonstrate good fetal penetration/ most protease inhibitors/ nelhnavir/ ritonavh/ saquinivir/ and lopinavir/ are known P-gp substrates and do not cross the placenta in detectable levels (98). 

The purpose of this chapter is provide an overview of the mechanisms for transport of two toxic metals, lead and cadmium, and to identify factors that may influence this process. The mechanisms for transfer of these two metals differ in that lead is readily diffusible across the placenta. There is no placental barrier for lead, whereas the placenta provides a protective barrier to fetal exposure to cadmium. Consideration of the placental transport of these two metals is prefaced by a few comments on possible experimental... 

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. 

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. 

The series of studies in which basic physiological parameters were varied may be used to point out which of these parameters most significantly affects placental oxygen transport. Additionally, these studies may be used with other solutions of the model in which several parameters are varied simultaneously to study possible control mechanisms which the mother-placenta-fetus system may have for maintaining adequate fetal oxygenation. 

In principle, chemicals arc capable of causing disturbances in placental functions at many different levels and via variable mechanisms. Potential mechanisms of action include interference of transport of essential nutrients and. substances by inhibiting specific transport proteins, inhibition of steroid... 

Riboflavin binding protein is not a typical membrane protein because it is soluble in plasma and transports riboflavin to the placental cells by a receptor and/or carrier mediated mechanism (Foraker et al. 2007). 

Additionally, passive diffusion was proven during riboflavin oversupplementation in small and large intestine, brain and renal cells. Receptor-mediated transport is suggested as an additional mechanism of riboflavin uptake and is recognised in both the small and large intestine and in placental cells. 

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