Alteration in Metabolism and Toxicity of Acetaminophen Upon Repeated Administration in Rats

  • Kim Sun J.
    College of Pharmacy, Seoul National University, Korea
  • Lee Min Y.
    College of Pharmacy, Seoul National University, Korea
  • Kwon Do Y.
    College of Pharmacy, Seoul National University, Korea
  • Kim Sung Y.
    College of Pharmacy, Wonkwang University, Korea
  • Kim Young C.
    College of Pharmacy, Seoul National University, Korea Research Institute of Pharmaceutical Sciences, Seoul National University, Korea

この論文をさがす

抄録

Our previous studies showed that administration of a subtoxic dose of acetaminophen (APAP) to female rats increased generation of carbon monoxide from dichloromethane, a metabolic reaction catalyzed mainly by cytochrome P450 (CYP) 2E1. In this study we examined the changes in metabolism and toxicity of APAP upon repeated administration. An intraperitoneal dose of APAP (500 mg/kg) alone did not increase aspartate aminotransferase, alanine aminotransferase, or sorbitol dehydrogenase activity in serum, but was significantly hepatotoxic when the rats had been pretreated with an identical dose of APAP 18 h earlier. The concentrations and disappearance of APAP and its metabolites in plasma were monitored for 8 h after the treatment. APAP pretreatment reduced the elevation of APAP-sulfate, but increased APAP-cysteine concentrations in plasma. APAP or APAP-glucuronide concentrations were not altered. Administration of a single dose of APAP 18 h before sacrifice increased microsomal CYP activities measured with p-nitrophenol, p-nitroanisole, and aminopyrine as probes. Expression of CYP2E1, CYP3A, and CYP1A proteins in the liver was also elevated significantly. The results suggest that administration of APAP at a subtoxic dose may result in an induction of hepatic CYP enzymes, thereby altering metabolism and toxicological consequences of various chemical substances that are substrates for the same enzyme system.<br>

収録刊行物

参考文献 (50)*注記

もっと見る

詳細情報

問題の指摘

ページトップへ