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Abstract
1. Isolated rat kidneys were perfused (single pass) with 4 to 40μM soln. of 4-dimethylamino[14C]phenol (DMAP).
2. Nephrotoxicity was not detected at concn. of 14C-DMAP up to 18μM; 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 of metabolites vs DMAP concn. followed Michaelis-Menten kinetics for DMAP-sulphate (Km 25μM, Vmax2.2nmol/min per g) and DMAP-thioethers (Km range 10–100μM, Vmax 4nmol/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.
