Relative Roles of Metabolism and Renal Excretory Mechanisms in Xenobiotic Elimination by Fish

Renal clearance techniques were used to examine the relative contributions of metabolism and renal tubular transport in determining the rates ofexcretion of benzo(a)pyrene (BaP) and several ofits phase I metabolites by southern flounder, Pmlichrhys kthoslgma.Each compound (31H-labeled) was injeted at a dose of2.5 gnole/kg, producing plasma concen- trations of 1 to 5 sM.Despite extensive plasma binding (>95%), the uncorrectd renal clearance of BaP-7$-dihydrodiol exceeded the glomerular filtration rate (GFR) by more than 20-fold.Phenolic BaP metabolites also showed net secretion (1.5-to 3-fold).At times prior to 3 hr, BaP itselfshowed an average clearance ofonly 02 times the GFR.After 3 hr, BaP cearance increased to three times the GFR.Decasing the dose ofBaP ijet also dramatically incesed its learance.Clearances ofall four compounds studied were reduced by probenecid and otber organic anion, including the herbicide 24-dichlorophenoxyacetic acid.HPLC analysis demonstrated that the bulk ofthe material excreted in the urine was not the parent compound, but sulfte or glucurnid conjugates ofits phenolic or dihydrodiolmeaites.Excretion ofsulfate conjugates predominated over the first 24 hr, whereas the glucuronide conjugates were the primary excretory products in succeeding days.In vitro, isolated renal tubules trnsported both glucuronide and sulfate conjuptes, but sulfates were the preferred substrates.Isolated tubules were shown to be capable of catalyzing conjugation reactions, producing predominantly glucuronide conjugates.Liver slices produced both types of conjugates.Thus, the rapid excretion of BaP-7,8dihydrodiol reflected a combination of two processes.First, this metabolite was rapidly converted to its sulfate conjugate, pimarily via etnrenal tissues.Second, the sulfate conjugate was preferentially transported to the urine yia secretion on the organic anion transport system.