Enhancement of acetaminophen-induced chronic hepatotoxicity in restricted fed rats: a nonclinical approach to acetaminophen-induced chronic hepatotoxicity in susceptible patients

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  • Kondo Kazuma
    Toxicology Research Lab., Central Pharmaceutical Research Institute, JAPAN TOBACCO INC.
  • Yamada Naohito
    Toxicology Research Lab., Central Pharmaceutical Research Institute, JAPAN TOBACCO INC.
  • Suzuki Yusuke
    Toxicology Research Lab., Central Pharmaceutical Research Institute, JAPAN TOBACCO INC.
  • Toyoda Kaoru
    Toxicology Research Lab., Central Pharmaceutical Research Institute, JAPAN TOBACCO INC.
  • Hashimoto Tatsuji
    Toxicology Research Lab., Central Pharmaceutical Research Institute, JAPAN TOBACCO INC.
  • Takahashi Akemi
    Toxicology Research Lab., Central Pharmaceutical Research Institute, JAPAN TOBACCO INC.
  • Kobayashi Akio
    Toxicology Research Lab., Central Pharmaceutical Research Institute, JAPAN TOBACCO INC.
  • Shoda Toshiyuki
    Toxicology Research Lab., Central Pharmaceutical Research Institute, JAPAN TOBACCO INC.
  • Kuno Hideyuki
    Toxicology Research Lab., Central Pharmaceutical Research Institute, JAPAN TOBACCO INC.
  • Sugai Shoichiro
    Toxicology Research Lab., Central Pharmaceutical Research Institute, JAPAN TOBACCO INC.

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Acetaminophen (APAP) is a commonly used and effective analgesic and antipyretic agent. However, some patients encounter hepatotoxicity after repeated APAP dosing at therapeutic doses. In the present study, we focused on the nutritional state as one of the risk factors of APAP-induced chronic hepatotoxicity in humans and investigated the contribution of undernourishment to susceptibility to APAP-induced chronic hepatotoxicity using an animal model mimicking undernourished patients. Rats were divided into 2 groups: the ad libitum fed (ALF) and the restricted fed (RF) rats and were assigned to 3 groups (n = 8/group) for each feeding condition. The animals were given APAP at 0, 300 and 500 mg/kg for 99 days under each feeding condition. Plasma and urinary glutathione-related metabolites and liver function parameters were measured during the dosing period and hepatic glutathione levels were measured at the end of the dosing period. In the APAP-treated ALF rats hepatic glutathione levels were increased and hepatic function parameters were not changed, but in the APAP-treated RF rats hepatic glutathione levels were decreased at 500 mg/kg and hepatic function parameters were increased at 300 and 500 mg/kg. Moreover the urinary endogenous metabolite profile after long-term treatment with APAP in the ALF and RF rats was similar to that in human non-responders and responders to APAP-induced chronic hepatotoxicity, respectively. In conclusion, the RF rats were more sensitive to APAP-induced chronic hepatotoxicity than the ALF rats and were considered to be a useful model to estimate the contribution of the nutritional state of patients to APAP-induced chronic hepatotoxicity.

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