Effects and metabolic pathway of 4-dimethylaminophenol during kidney perfusion

1. Isolated rat kidneys were perfused (single pass) with 4 to 40 microM soln. of 4-dimethylamino[14C]phenol (DMAP). 2. Nephrotoxicity was not detected at concn. of 14C-DMAP up to 18 microM; higher conc. resulted in irreversible loss of physiological functions with simultaneous five-fold increase in covalently bound 14C. 3. At all concn., 85% of the post-renal 14C was due to unchanged DMAP, while 15% corresponded to DMAP conjugates. These conjugates were identified as DMAP-glucuronide (90% total), DMAP-sulphate and DMAP-thioethers. 4. All DMAP conjugates were conc. in the urine with urine/perfusate concn. ratios in the range 5-7 for the glucuronide, 50-100 for the sulphate, and 10-20 for the thioethers. 5. Rates of formation fo metabolites vs DMAP concn. followed Michaelis-Menten kinetics for DMAP-sulphate (Km 25 microM, Vmax 2.2 nmol/min per g) and DMAP-thioethers (Km range 10-100 microM, Vmax 4 nmol/min per g). DMAP-glucuronide formation rate increased linearly with DMAP concn. and showed a four-fold increase at toxic DMAP doses. 6. From the data for DMAP conjugation capacity, urine/perfusate concn. ratios of DMAP conjugates and microautoradiography, it is suggested that DMAP conjugation is located mainly in the proximal convoluted tubule, where deterioration of renal functions originates.