Evidence against deacetylation and for cytochrome P450-mediated activation in acetaminophen-induced nephrotoxicity in the CD-1 mouse.
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.
Emeigh Hart
S G
SG
Department of Pharmacology, University of Connecticut, Storrs 06269-2092.
Beierschmitt
W P
WP
Bartolone
J B
JB
Wyand
D S
DS
Khairallah
E A
EA
Cohen
S D
SD
D000082:Acetaminophen / Q000378:metabolism / Q000633:toxicity*; D000107:Acetylation / Q000187:drug effects; D000627:Aminophenols / Q000633:toxicity; D000818:Animals; D001806:Blood Urea Nitrogen; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D007683:Kidney Tubular Necrosis, Acute / Q000139:chemically induced / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000648:ultrastructure; D008297:Male; D051379:Mice; D009596:Nitrophenols / Q000494:pharmacology; D010882:Piperonyl Butoxide / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D014317:Tritolyl Phosphates / Q000494:pharmacology
D000627:Aminophenols; D065607:Cytochrome P-450 Enzyme Inhibitors; D009596:Nitrophenols; D011506:Proteins; D014317:Tritolyl Phosphates; D000082:Acetaminophen; C002887:bis(4-nitrophenyl)phosphate; D003577:Cytochrome P-450 Enzyme System; D010882:Piperonyl Butoxide; C026729:4-aminophenol; C025541:tri-o-cresyl phosphate