nitrophenols and tri-o-cresyl-phosphate

Acetaminophen (APAP) administration (600 mg/kg, po) results in proximal tubular necrosis in 18-hr fasted, 3-month-old male CD-1 mice. This study was undertaken to determine if deacetylation of APAP to p-aminophenol (PAP) is a prerequisite to nephrotoxicity in the mouse, as it is in the Fischer rat. Administration of either APAP or PAP to mice resulted in significant elevations of plasma urea nitrogen and marked proximal tubular necrosis at 12 hr after dosing. Prior inhibition of APAP deacetylation by the carboxylesterase inhibitors bis(p-nitrophenyl) phosphate or tri-o-tolyl-phosphate did not alter APAP hepatotoxicity or nephrotoxicity. By contrast, pretreatment with the MFO inhibitor piperonyl butoxide decreased APAP nephrotoxicity but not that of PAP. Immunochemical analysis of kidneys from APAP-treated mice demonstrated covalently bound APAP but no binding was detected after mice were treated with a nephrotoxic dose of PAP. Since the antibody used has been characterized as being directed primarily against the N-acetyl moiety of bound APAP metabolite and since it did not react with kidney proteins of mice given a nephrotoxic dose of PAP, it is unlikely that APAP deacetylation preceded binding or that acetylation of bound PAP occurred. Taken together, these findings indicate that in the CD-1 mouse, APAP-induced nephrotoxicity differs from that previously described for the Fischer rat and likely involves cytochrome P450-dependent activation and subsequent covalent binding of a metabolite without prior deacetylation.

Topics: Acetaminophen; Acetylation; Aminophenols; Animals; Blood Urea Nitrogen; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Kidney Diseases; Kidney Tubular Necrosis, Acute; Kidney Tubules, Proximal; Male; Mice; Nitrophenols; Piperonyl Butoxide; Proteins; Tritolyl Phosphates

Nasal tissues contain large amounts of carboxylesterase but its precise role in metabolism of inspired ester vapors is not known. The current study was aimed at quantitating the extent of metabolism of inspired ethyl acetate in the upper respiratory tract (URT) of the F344 rat and Syrian hamster. Ethyl acetate deposition was measured in the surgically isolated URT of these species under constant velocity unidirectional flow conditions. The degree of metabolism was estimated by mathematic modeling based on a simple venous-equilibration approach and by direct comparison of deposition efficiencies in naive and carboxylesterase-inhibited animals. Ethyl acetate deposition efficiencies averaged between 10 and 35% in the rat URT and 36 and 72% in the hamster. Carboxylesterase inhibition decreased deposition in both species. Both the modeling efforts and the direct comparisons between naive and inhibited animals indicated that significant amounts of the deposited ethyl acetate were metabolized in the URT of both species with the extent of metabolism being more pronounced in the hamster. Specifically, 40-65% of the deposited ethyl acetate was metabolized in the URT of the rat compared to 63-90% in the hamster. This first-pass metabolism (i) increased URT deposition efficiencies; (ii) led to production of high metabolite levels in URT tissues; and (iii) decreased the amount of parent ethyl acetate available for absorption into the bloodstream in the URT.

Topics: Acetates; Acetone; Animals; Carboxylic Ester Hydrolases; Cricetinae; Hydrolysis; Kinetics; Male; Mesocricetus; Nasal Cavity; Nitrophenols; Rats; Rats, Inbred F344; Tritolyl Phosphates