Abstract
BackgroundIn the present study, 2-tert-butyl-4-chloro-5-[6-(4-18F-fluorobutoxy)-pyridin-3-ylmethoxy]-2H-pyridazin-3-one (18F-BCPP-BF), a PET probe for mitochondrial complex I (MC-I), was used to validate whether MC-I is a useful biomarker for detecting acetaminophen-induced dysfunctions in the liver and kidney.The kinetic and distribution of 18F-BCPP-BF were assessed in rats using high-resolution animal PET in vivo. The binding specificity of 18F-BCPP-BF to MC-I in the liver and kidney was confirmed by the pre-administration of rotenone, a specific MC-I inhibitor. The effects of acetaminophen on MC-I activity were assessed 2 and 24 h after the administration of vehicle or acetaminophen at a dose of 100 or 300 mg/kg. Biochemical parameters in plasma and urine were assessed 2, 6, and 24 h after the administration of vehicle or acetaminophen.ResultsThe uptake of 18F-BCPP-BF by the liver and kidney was significantly inhibited by the pre-administration of rotenone. Two and more hours after the administration of acetaminophen, the uptake of 18F-BCPP-BF was dose-dependently reduced in the liver, even at 100 mg/kg, and in the kidney at 300 mg/kg, whereas biological parameters started to be affected 6 h or later at doses of 300 mg/kg.ConclusionsThe present study demonstrated that 18F-BCPP-BF has potential as a PET probe for the quantitative imaging of hepatic and renal dysfunction as impaired MC-I activity in the early phase of the treatment for an overdose of acetaminophen in the living body with PET.
Highlights
In the present study, 2-tert-butyl-4-chloro-5-[6-(4-18F-fluorobutoxy)-pyridin-3-ylmethoxy]-2H-pyridazin-3one (18F-BCPP-BF), a PET probe for mitochondrial complex I (MC-I), was used to validate whether MC-I is a useful biomarker for detecting acetaminophen-induced dysfunctions in the liver and kidney
The immunoprecipitation of mitochondrial superoxide dismutase (MnSOD), a critical enzyme in the detoxification of reactive oxygen species (ROS), from the livers of acetaminophen-treated mice did not detect acetaminophen-MnSOD adducts [9]. These findings suggest that the production of N-acetyl-p-benzoquinone imine (NAPQI) is not the only reason for acetaminophen-induced liver necrosis and that cytochrome P450 2E1 (CYP2E1) may have a limited role in the formation of NAPQI at higher doses of acetaminophen [10]
With the pre-administration of rotenone at a dose of 0.1 mg/kg/h, the uptake level of 18F-BCPP-BF calculated as averaged Standard uptake value (SUV) from 15 to 30 min postinjection was markedly reduced in the liver (76.9%/p = 0.038 vs. control) and renal cortex (64.2%/p = 0.027 vs. control) than in the control (Figs. 1b and 2b)
Summary
2-tert-butyl-4-chloro-5-[6-(4-18F-fluorobutoxy)-pyridin-3-ylmethoxy]-2H-pyridazin-3one (18F-BCPP-BF), a PET probe for mitochondrial complex I (MC-I), was used to validate whether MC-I is a useful biomarker for detecting acetaminophen-induced dysfunctions in the liver and kidney. The effects of acetaminophen on MC-I activity were assessed 2 and 24 h after the administration of vehicle or acetaminophen at a dose of 100 or 300 mg/kg. The electron transport chain in mitochondria, which consists of five complexes from I to V, is the major site of ATP production. Among these complexes, the complex I (MC-I) is the first and rate-limiting step of the overall respiratory activity and oxidative phosphorylation under physiological conditions. In the USA, an overdose of acetaminophen is responsible for approximately 56,000 emergency room visits, 26,000 hospitalizations, and nearly 500 deaths each year [5]
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