Habitual use of acetaminophen as a risk factor for chronic renal failure: A comparison with phenacetin

Buckalew, Vardaman M.

doi:10.1016/s0272-6386(96)90562-4

Cited by 19 publications

(6 citation statements)

References 25 publications

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“…PAP, a hydrolyzed metabolite of APAP, was also demonstrated to be a nephrotoxicant in rat (Newton et al, 1982). APAP is known to cause renal failure in humans, although the risk is much lower than that for phenacetin (Buckalew, 1996). However, it is unknown whether PAP is associated with APAP-induced renal failures in humans.…”

Section: Discussionmentioning

confidence: 99%

Arylacetamide Deacetylase Is a Determinant Enzyme for the Difference in Hydrolase Activities of Phenacetin and Acetaminophen

Watanabe

Fukami²,

Takahashi³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Phenacetin was withdrawn from the market because it caused renal failure in some patients. Many reports indicated that the nephrotoxicity of phenacetin is associated with the hydrolyzed metabolite, p-phenetidine. Acetaminophen (APAP), the major metabolite of phenacetin, is also hydrolyzed to p-aminophenol, which is a nephrotoxicant. However, APAP is safely prescribed if used in normal therapeutic doses. This background prompted us to investigate the difference between phenacetin and APAP hydrolase activities in human liver. In this study, we found that phenacetin is efficiently hydrolyzed in human liver microsomes (HLM) [CL int 1.08 ؎ 0.02 l/(min ⅐ mg)], whereas APAP is hardly hydrolyzed [0.02 ؎ 0.00 l/(min ⅐ mg)]. To identify the esterase involved in their hydrolysis, the activities were measured using recombinant human carboxylesterase (CES) 1A1, CES2, and arylacetamide deacetylase (AADAC). Among these, AADAC showed a K m value (1.82 ؎ 0.02 mM) similar to that of HLM (3.30 ؎ 0.16 mM) and the highest activity [V max 6.03 ؎ 0.14 nmol/(min ⅐ mg)]. In contrast, APAP was poorly hydrolyzed by the three esterases. The large contribution of AADAC to phenacetin hydrolysis was demonstrated by the prediction with a relative activity factor. In addition, the phenacetin hydrolase activity by AADAC was activated by flutamide (5-fold) as well as that in HLM (4-fold), and the activity in HLM was potently inhibited by eserine, a strong inhibitor of AADAC. In conclusion, we found that AADAC is the principal enzyme responsible for the phenacetin hydrolysis, and the difference of hydrolase activity between phenacetin and APAP is largely due to the substrate specificity of AADAC.

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Section: Discussionmentioning

confidence: 99%

Arylacetamide Deacetylase Is a Determinant Enzyme for the Difference in Hydrolase Activities of Phenacetin and Acetaminophen

Watanabe

Fukami²,

Takahashi³

et al. 2010

Drug Metab Dispos

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“…This led to successive legislative measures; in Sweden phenacetin became a prescription drug in 1961 and thereafter it was gradually removed from the market. The availability was restricted in several other countries during the following decade 189 . Soon, several objections against "the phenacetin nephropathy concept" were raised; numerous animal studies with phenacetin failed to produce renal papillary necrosis whereas other analgesics did, the removal of phenacetin in some countries did not reduce the incidence of AAN, and the prognosis for AAN was better if all analgesic were discontinued and not only phenacetin 180 .…”

Section: Which Analgesic(s) Is Nephrotoxic?mentioning

confidence: 99%