Cysteine conjugate transport is an important determinant of the pharmacology and disposition of drugs and xenobiotics during mercapturic acid biosynthesis. The disposition is extremely complex since it involved liver, kidney, intestine and two possible routes of excretion, urine and feces. Through, the shuttling of mercapturic acid intermediates appears to be directed, the mechanisms which organize the transport are not clearly defined. Preliminary data suggests that functional and kinetic properties of transporters which are polarized to different membrane locations. The purpose of this research is to elucidate the relationship between the organ specific pharmacology and toxicology of cysteine conjugates and their transport. Isolated cells from liver, kidney and intestine will be prepared and the transport of cysteine conjugates will be characterized. The reversibility, ion dependence, energy dependence and kinetic parameters will be defined in the isolated cells. Similar data will be collected for isolated membrane vesicles from defined domains of plasma membrane of liver, kidney and intestine. The membrane data will establish the polarity of specific transport systems. The data will be used to construct a model which will both explain and predict the pharmacological specificity of cysteine conjugate in vivo. The premise of the working model is that the directed interorgan shuttling can be explained based on polarity, reversibility and affinity. Many of these conjugates have potent and organ specific pharmacological and toxicological properties.
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