Circulating liver-specific microRNAs in cynomolgus monkeys

• Published in: Journal of Toxicologic Pathology Vol. 31; no. 1; pp. 3 - 13
• Main Authors: Iguchi, Takuma, Sakurai, Ken, Tamai, Satoshi, Mori, Kazuhiko
• Format: Journal Article
• Language: English; Japanese
• Published: Japan JAPANESE SOCIETY OF TOXICOLOGIC PATHOLOGY 01.01.2018; The Japanese Society of Toxicologic Pathology; Japan Science and Technology Agency; Japanese Society of Toxicologic Pathology
• Subjects: Acetaminophen; Analgesics; Biomarkers; cynomolgus monkeys; drug-induced liver injury; Hepatocytes; Hepatotoxicity; Intestine; Kidneys; Liver; microRNA; MicroRNAs; miRNA; Monkeys; Necrosis; Next-generation sequencing; Polymerase chain reaction; Primates; Reverse transcription; Toxicity testing; Variation; drug-induced liver injury; microRNA; cynomolgus monkeys; next-generation sequencing
• ISSN: 0914-9198; 1881-915X; 1347-7404
• DOI: 10.1293/tox.2017-0036

Circulating microRNAs (miRNAs) can potentially be used as sensitive and specific biomarkers for tissue injury. However, the usefulness of circulating miRNAs as safety biomarkers in nonclinical toxicological studies using nonhuman primates is debatable owing to the limited information on organ-specific miRNAs. Therefore, a systematic investigation was performed to address this point. We identified organ-specific miRNAs from cynomolgus monkeys by next-generation sequencing analysis, which revealed that miR-122 was only abundant in the liver, whereas miR-192 was abundant in the liver, stomach, intestines, and kidney. The sequences of these miRNAs were identical to their human counterparts. Next, the absolute miR-122 and miR-192 levels were qualified by quantitative reverse transcription polymerase chain reaction (RT-qPCR) to determine the circulating levels of the miRNAs. No significant differences in the levels of circulating miRNAs between sexes were noted, and there was greater interindividual variation in miR-122 (20-fold variation) than in miR-192 (8-fold variation), based on their dynamic ranges. Finally, we evaluated the fluctuation in circulating liver-specific miRNAs in a monkey model of acetaminophen-induced hepatotoxicity. Acetaminophen with L-buthionine-(S,R)-sulfoximine induced hepatotoxicity in all the animals, which was characterized histopathologically by centrilobular necrosis and vacuolation of hepatocytes. Circulating miR-122 and miR-192 levels increased more than ALT levels after 24 h, indicating that circulating miR-122 and miR-192 may serve as sensitive biomarkers for the detection of hepatotoxicity in cynomolgus monkeys. This review describes the fundamental profiles of circulating liver-specific miRNAs in cynomolgus monkeys and focusses on their organ specificity, circulating levels, and fluctuations in drug-induced hepatotoxicity.