Differential diagnosis of chemical-induced hepatobiliary toxicities using a new hepatobiliary imaging agent in mice

초록

ABSTRACT: We have synthesized ⁹⁹ᵐTc-mercaptoacetyltriglycine (MAG3)-biocytin as a new imaging agent for hepatobiliary scintigraphy. The aim of this study was to evaluate the usefulness of ⁹⁹ᵐTc-MAG3-biocytin scintigraphy in differentiating carbon tetrachloride (CCl₄)-induced hepatotoxicity from α-naphthylisothiocyanate (ANIT)-induced cholestasis in mice, which reflects the differential diagnosis of neonatal jaundice caused by neonatal hepatitis and congenital biliary atresia in humans. Methods: Balb/c mice (female, 20 g, n = 4–6) were pretreated with CCl₄ (0.5 or 1.0 mL/kg) and ANIT (150 or 300 mg/kg) 18 h before scintigraphy. Biochemical and histopathological examinations showed a pattern of typical acute hepatitis (increase of transaminases and hepatocellular necrosis) in CCl₄-treated mice and cholestasis (increase of alkaline phosphatase and γ-glutamyltransferase, and biliary hyperplasia) in ANIT-treated mice, respectively. Mice were fasted for at least 4 h prior to the intravenous injection of ⁹⁹ᵐTc-MAG3-biocytin (18.5 MBq/20 µg) in 2% human serum albumin in saline. Scintigraphy was performed with a γ-camera equipped with a 1 mm diameter pinhole collimator for 30 min, and images were acquired every 15 s. We compared the values of physical parameters, such as peak liver/heart ratio (rmax) and peak ratio time (tmax), for ⁹⁹ᵐTc-MAG3-biocytin scintigraphy. Results: Scintigraphic parameters of the CCl₄-pretreated (0.5 mL/kg) group showed an 81.9% decrease in rmax and a 42.2% decrease in tmax, whereas the ANIT-pretreated (150 mg/kg) group showed a 53% decrease in rmax and a 2.36-fold increase in tmax (P < 0.05). These results demonstrate that the decrease in rmax and the shortening of tmax are characteristic features of hepatotoxicity, in contrast to the increase in tmax and decrease in rmax for biliary hyperplasia. Conclusion: ⁹⁹ᵐTc-MAG3-biocytin hepatobiliary scintigraphy can distinguish hepatitis from cholestasis in a mouse model and may be similarly useful in humans for differentiating the cause of neonatal jaundice in clinical studies.

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