A monkey model of acetaminophen-induced hepatotoxicity; phenotypic similarity to human

Abstract

Species-specific differences in the hepatotoxicity of acetaminophen (APAP) have been shown. To establish a monkey model of APAP-induced hepatotoxicity, which has not been previously reported, APAP at doses up to 2,000 mg/kg was administered orally to fasting male and female cynomolgus monkeys (n = 3-5/group) pretreated intravenously with or without 300 mg/kg of the glutathione biosynthesis inhibitor, L-buthionine-(S,R)-sulfoximine (BSO). In all the animals, APAP at 2,000 mg/kg with BSO but not without BSO induced hepatotoxicity, which was characterized histopathologically by centrilobular necrosis and vacuolation of hepatocytes. Plasma levels of APAP and its reactive metabolite N-acethyl-p-benzoquinone imine (NAPQI) increased 4 to 7 hr after the APAP treatment. The mean C level of APAP at 2,000 mg/kg with BSO was approximately 200 µg/mL, which was comparable to high-risk cutoff value of the Rumack-Matthew nomogram. Interestingly, plasma alanine aminotransferase (ALT) did not change until 7 hr and increased 24 hr or later after the APAP treatment, indicating that this phenotypic outcome was similar to that in humans. In addition, circulating liver-specific miR-122 and miR-192 levels also increased 24 hr or later compared with ALT, suggesting that circulating miR-122 and miR-192 may serve as potential biomarkers to detect hepatotoxicity in cynomolgus monkeys. These results suggest that the hepatotoxicity induced by APAP in the monkey model shown here was translatable to humans in terms of toxicokinetics and its toxic nature, and this model would be useful to investigate mechanisms of drug-induced liver injury and also potential translational biomarkers in humans.

miRNA-122 Protects Mice and Human Hepatocytes from Acetaminophen Toxicity by Regulating Cytochrome P450 Family 1 Subfamily A Member 2 and Family 2 Subfamily E Member 1 Expression

“…Most of these new agents are tested in rodent models. It will be more informative to test these chemical inhibitors along miRNA-based therapeutics in the newly developed models, such as pig 41 and monkey, 42 and ex vivo human liver model 43 that mimic acetaminophen toxicity in humans.…”

How to translate neuro-cognitive and behavioural outcome data in animals exposed to paracetamol to the human perinatal setting?

“…For sheep, a chronically catheterized fetal sheep model to assess effects of non-narcotic analgesics has been described, while this species has been used to assess the impact of steroids on the developing brain [53,54]. As a final illustration, the fetal neurotoxicity of dexmedetomidine has been studied in a pregnant cynomolgus monkey model, as well as a paracetamol hepatotoxicity model in the same species [55,56].…”

Circulating liver-specific microRNAs in cynomolgus monkeys

“…However, little is known about drug-induced hepatotoxic signatures or circulating hepatic biomarker profiles in cynomolgus monkeys. Therefore, we established a monkey model of APAP-induced hepatotoxicity to attain a better understanding of the fluctuation of circulating miRNAs as potential hepatotoxic biomarkers 32 .…”

“…5. Time course of plasma acetaminophen (APAP) and N -acetyl- p -benzoquinone imine (NAPQI) concentrations 32 . The animals were given acetaminophen at 300, 1,000, or 2,000 mg/kg with L-buthionine-(S,R)-sulfoximine (BSO; 300 mg/kg).…”

“…6. Fluctuations in the levels of plasma ALT, miR-122, and miR-192 32 . Acetaminophen (APAP; 2,000 mg/kg) was orally administered to animals 1 h after pretreatment with an intravenous injection of L-buthionine-(S,R)-sulfoximine (BSO; 300 mg/kg).…”