Placenta substrates

Within the OAT family, OAT4 is the only transporter expressed at appreciable levels in both the placenta and in the kidney [54]. The membrane localization of OAT4 within these tissues has not been examined. Steroid sulfates, and ochratoxinA are efficient transport substrates of OAT4, whereas PAH is weakly transported [54]. The functional importance of OAT4 in regulating placental permeability and renal drug elimination is currently unknown. 

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. 

Alkaline phosphatase is an enzyme represented by various isoforms in many tissues such as liver, bone, intestine, placenta, some tumors and in leukocytes. Addition of 1 mM levamisole to the chromogen/substrate will inhibit endogenous alkaline phosphatase activity, with the exception of the intestinal isoform. If necessary, this can be blocked with a weak acid wash, such as 0.03 0.5 N HC1 or 1 M citric acid. 

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. 

MAOIs act by mitigating the actions of monoamine oxidase in the neuron and increasing monoamine content. There are two forms of monoamine oxidase. MAO-A is present in both dopamine and norepinephrine neurons and is found primarily in the brain, gut, placenta, and liver its primary substrates are norepinephrine, epinephrine, and serotonin. MAO-B is found primarily in serotonergic and histaminergic neurons and is distributed in the brain, liver, and platelets. MAO-B acts primarily on tyramine, phenylethylamine, and benzylamine. Both MAO-A and -B metabolize tryptamine and dopamine. 

Lipophilic compounds will cross the placenta most readily by passive diffusion, whereas those ionized at plasma pH will generally not, unless they are substrates for a carrier-mediated transport system. Most foreign compounds will enter the embryonic bloodstream by passive diffusion, and the exposure of the embryo of fetus will therefore depend on the concentration of the compound in the maternal bloodstream and the blood flow, which increases as pregnancy progresses. The ability of the maternal organism to metabolize and excrete the compound, reflected in the plasma level and half-life, will therefore be a major determinant of... 

Failure in the placental transport of essential substrates may be teratogenic and can be caused by certain compounds such as azo dyes. This has, however, only been demonstrated in rodents because of the inverted yolk sac type of placenta such animals have. 

The last treatment is the most gentle and should be used for labile antigens 2 For alkaline phosphatase, incubate the section in 20% acetic acid for 5 min, and then wash it in tap water. This treatment may destroy the antigen. An alternative for tissues other than the intestine is to make the substrate solution (Section 3.2.2.) in 1 mM levamisole (increase to 2 mM for tissues rich in alkaline phosphatase, e.g, kidney or placenta) see Note 10)... 

Diamine Oxidases. Diamine oxidases are enzymes that also oxidize amines to aldehydes. The preferred substates are aliphatic diamines in which the chain length is four (putrescine) or five (cadaverine) carbon atoms. Diamines with carbon chains longer than nine will not serve as substrates but can be oxidized by monoamine oxidases. Secondary and tertiary amines are not metabolized. Diamine oxidases are typically soluble pyridoxal phosphate-containing proteins that also contain copper. They have been found in a number of tissues, including liver, intestine, kidney, and placenta. 

Although the CYP enzymes are the most abundant in the liver, they are also present in other tissues including the skin, kidney, intestine, lung, placenta, and nasal mucosa. Because CYP exists as multiple isozymes with different substrate specificities, the presence or absence of a particular CYP isozyme may contribute to tissue-specific toxicities. Many drugs and other foreign compounds are known to induce one or more of the CYP isozymes, resulting in an increase, decrease, or an alteration in the metabolic pathway of chemicals metabolized by the CYP isozymes involved. Specific examples of these types of interactions are given later in this section. 

Drug metabolism can occur in all tissues and most biological fluids. However, the widest range of metabolic reactions occurs in the liver. A more substrate-selective range of metabolic processes takes place in the kidney, lungs, brain, placenta and other tissues. 

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