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Tolerance to Acetaminophen Hepatotoxicity in the Mouse Model of Autoprotection is Associated with Induction of Flavin-containing Monooxygenase-3 (FMO3) in Hepatocytes
Citation:
Rudraiah, S., P. Rohrer, I. Gurevich, M. Goedken, T. Rasmussen, R. Hines, AND J. Manautou. Tolerance to Acetaminophen Hepatotoxicity in the Mouse Model of Autoprotection is Associated with Induction of Flavin-containing Monooxygenase-3 (FMO3) in Hepatocytes. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 141(1):263-277, (2014).
Impact/Purpose:
The purpose of this research was to evaluate a role for the enzyme, FMO3, in mediating autoprotection to acetominophen exposure. Given that this same phenomenon also is observed with some environmental toxicants, better understanding of the mechanisms underlying autoprotection is of some interest to the Agency.
Description:
Acetaminophen (APAP) pretreatment with a low hepatotoxic dose in mice results in resistance to a second, higher dose of APAP (APAP autoprotection). Recent microarray work by our group showed a drastic induction of liver flavin containing monooxygenase-3 (Fmo3) mRNA expression in our mouse model of APAP autoprotection. Hepatic expression of the Fmo3 gene is highly variable and is important in the detoxification of xenobiotics. We hypothesized that induction of Fmo3 plays an important role in protecting against APAP hepatotoxicity in the model of APAP autoprotection. The purpose of this study was to characterize the gene regulation and protein expression of liver Fmo3 during APAP hepatotoxicity. The functional consequences of Fmo3 induction were also investigated. Plasma and livers were collected from male C57BL/6J mice over a period of 72h following a single dose of APAP (400 mg/kg) to measure Fmo3 mRNA and protein expression. Although Fmo3 mRNA levels increased significantly following APAP treatment, its protein expression marginally changed. By contrast, both Fmo3 mRNA and protein expression were significantly higher in mice pretreated with APAP (400 mg/kg) and re-exposed to a higher dose (600 mg/kg). In agreement with greater Fmo3 protein expression in livers of autoprotected mice, its catalytic activity was also significantly higher. In contrast to naïve C57BL/6J male mice, female mice have about 80-times higher basal Fmo3 mRNA and are highly resistant to APAP hepatotoxicity. Coadministration of APAP with the FMO inhibitor methimazole rendered female mice susceptible to APAP hepatotoxicity, with no changes in susceptibility detected in male mice. Furthermore, a human hepatocyte cell line (HC-04) clone overexpressing human FMO3 showed enhanced resistance to APAP cytotoxicity. Taken together, these findings establish for the first time induction of Fmo3 protein expression and function by xenobiotic treatment. Our results also indicate that Fmo3 expression and function plays a role in protecting the liver from APAP-induced toxicity. Although the mechanism(s) of this protection remains to be elucidated, this work describes a novel function for this enzyme.
