Use of 99mTc-mercaptoacetyltriglycine (MAG3)-biocytin hepatobiliary scintigraphy to study the protective effect of a synthetic enzyme inhibitor on acute hepatotoxicity in mice.
Recent data suggest that inhibitors of ethanol-inducible cytochrome P450 (CYP2E1) can protect the liver from injury caused by various substrates of CYP2E1. In this study, we measured the protective effect of isopropyl-2-(1,3-dithioetane-2-ylidene)-2[N-(4-methylthiazol -2-yl)-carbamoyl]acetate (YH439), a transcriptional inhibitor of CYP2E1, against carbon tetrachloride (CCl4)-induced hepatotoxicity by using various conventional methods and dynamic scintigraphy with 99mTc-mercaptoacetyltriglycine (MAG3)-biocytin, a recently developed scintigraphic agent. Balb/c mice were pretreated with two doses of YH439 (50 or 150 mg/kg per day) at 48 h and 24 h and one dose of CCl4 (0.25 mL/kg) at 18 h before scintigraphy. The results were compared with those of two other groups, one that received CCl4 but not YH439, and the other that received neither (control). Scintigraphic images were acquired continuously at 15-sec intervals for 30 min. Pharmacokinetic parameters, such as peak liver/heart ratio (r(max)), peak liver uptake time (t(max)), and hepatic half-clearance time (HCT), were obtained from time-activity curves derived from regions-of-interest (ROI) over the liver and the heart. Acute administration of CCl4 alone caused centrilobular necrosis and serum transaminase levels to rise more than 5 times higher than those of the control group. Pharmacokinetic parameters also changed significantly from those of the control group. Administration of YH439 prevented centrilobular necrosis and significantly improved pharmacokinetic parameters. This study demonstrates for the first time that hepatobiliary scintigraphy can be used to study in vivo biochemistry of the CYP2E1 inhibitor (YH439) against liver toxicity.
Kim
M K
MK
Department of Nuclear Medicine, Warren G. Magnuson Clinical Center, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA.
Song
B J
BJ
Seidel
J
J
Soh
Y
Y
Jeong
K S
KS
Kim
I S
IS
Kobayashi
H
H
Green
M V
MV
Carrasquillo
J A
JA
Paik
C H
CH
D000818:Animals; D001659:Biliary Tract / Q000000981:diagnostic imaging*; D002251:Carbon Tetrachloride / Q000037:antagonists & inhibitors / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D008099:Liver / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000473:pathology; D008107:Liver Diseases / Q000000981:diagnostic imaging* / Q000517:prevention & control*; D008239:Lysine / Q000031:analogs & derivatives*; D051379:Mice; D008807:Mice, Inbred BALB C; D009336:Necrosis; D015609:Organotechnetium Compounds; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals; D013844:Thiazoles / Q000627:therapeutic use*
D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004791:Enzyme Inhibitors; D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; D013844:Thiazoles; C098009:YH 439; C107877:technetium Tc 99m MAG3-biocytin; D002251:Carbon Tetrachloride; D019392:Cytochrome P-450 CYP2E1; D008239:Lysine