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Directing Role of Organic Anion Transporters in the Excretion of Mercapturic Acids of Alkylated Polycyclic Aromatic Hydrocarbons

German Institute of Human Nutrition Potsdam-Rehbrücke, Department of Nutritional Toxicology, Nuthetal, Germany (N.B., M.B., J.L., B.H.M., W.E., H.R.G.); and Biochemical Institute for Environmental Carcinogens, Grosshansdorf, Germany (H.F., A.S.)

Excretion of mercapturic acids of a xenobiotic is a good indicator for the formation of electrophilic intermediates. However, the route of excretion, urine or feces, is important for usage of a given mercapturic acid as a biomarker in humans. In the present study we investigated the excretion routes of 1-methylpyrenyl mercapturic acid (MPMA) and 1,8-dimethylpyrenyl mercapturic acid (DMPMA) formed from the corresponding benzylic alcohols in rats. Whereas MPMA was primarily excreted in urine (72% of the total urinary and fecal level), DMPMA clearly preferred the fecal route (88%). We then examined interactions of these mercapturic acids with renal basolateral organic anion transporters (OATs) using HEK293 cells stably expressing human OAT1 and OAT3. The uptake rates of MPMA by OAT1- and OAT3-expressing cells were 2.8- and 1.7-fold, respectively, higher than that by control cells. MPMA was a competitive inhibitor of p-aminohippurate uptake by OAT1 and estrone sulfate uptake by OAT3 with K_i values of 14.5 µM and 1.5 µM, respectively. In contrast, DMPMA was not transported by OAT1 and only modestly transported by OAT3 (1.25-fold over control). Thus, we suspect that the substrate specificities, alone or together with other factors, played a directing role in the excretion of MPMA and DMPMA. Although the mechanistic link requires verification, our results clearly show that a minute structural difference (the presence or absence of an additional methyl group in an alkylated four-ring polycyclic hydrocarbon) can strongly affect the interaction with transporter proteins and direct the excretion route of mercapturic acids.