Effect of Ginkgo biloba on acetaminophen-induced hepatotoxicity in male Long-Evans rats

Acetaminophen (APAP) is commonly used as an analgesic and an antipyretic. This drug is considered safe, but it may cause severe hepatotoxicity and even fatality in certain situations. Ginkgo biloba extract (GBE), which is a popular herbal medicine used mainly to improve memory, induces rat hepatic cytochrome P450 (CYP) enzymes, including CYP1A2, CYP2E1, and CYP3A. APAP is bioactivated by these enzymes to the hepatotoxic metabolite, N-acetyl-p-benzoquinoneimine. Hence, GBE may modulate APAP-induced hepatotoxicity. The current study investigated the influence of GBE (containing 6.2% w/w terpene trilactones and 21 % w/w flavonol glycosides) on APAP-induced hepatotoxicity in male Long-Evans rats, as assessed by liver histological analysis and plasma alanine aminotransferase (ALT) levels. The validated plasma ALT assay was accurate, precise, and reproducible, although it had poor sensitivity and a narrow dynamic range. Control experiments indicated that 20% Tween 80 in 0.9% NaCl (the vehicle used to suspend APAP) did not increase plasma ALT levels, fasting was required to elicit APAP-induced hepatotoxicity, and maximal plasma ALT levels were obtained with APAP at a dosage of 1000 mg/kg. GBE (500 mg/kg ip once daily for 8 days) did not increase plasma ALT levels, when compared to the 0.9% NaCl-treated control group, although histological analysis of hepatic tissues from GBE-treated rats showed that four of the five samples exhibited steatosis, necrosis, capsular inflammation, or sinusoidal dilatation. By comparison, GBE pretreatment (500 mg/kg ip once daily for 9 days) prevented the increase in plasma ALT levels in rats administered APAP (1000 mg/kg ip). The plasma ALT levels were 41 ± 3 U/L (mean ± SEM), 114 ± 22 U/L, and 53 ± 7 U/L in the vehicle-treated control group, APAP-treated group, and GBE and APAP-treated group, respectively. In contrast, GBE was not able to attenuate the occurrence of steatosis, necrosis, capsular inflammation, or sinusoidal dilatation. These effects were accompanied by an increase (5-fold) in hepatic CYP3A23 mRNA expression, but no change in UDP-glucuronosy1transferase 1A6 mRNA expression. In summary, based on histological assessment, GBE exacerbated APAP-induced hepatotoxicity in male Long-Evans rats, and this might be related to increased bioactivation rather than reduced glucuronidation of APAP by GBE.Pharmaceutical Sciences, Faculty ofGraduat