aim of this research is to determine the way in which cocaine and morphine produce liver damage. The metabolism of cocaine will be studied in mice in order to establish the mature of the active metabolite that is responsible for liver damage. Dye uptake studies will be used to measure changes in liver function. Isolated livers will be employed to examine the effects of cocaine on perfusion and bile secretion. The mobilization of calcium in isolated hepatocytes will be measured fluorometrically. Changes in blood levels of catecholamines and serotonin will be assayed at various time after cocaine and morphine. Adrenergic and serotonergic agonists and antagonists will be used to modify the extent of liver damage after cocaine and narcotic drugs. Nuclear magnetic resonance spectroscopy will be applied to follow the metabolism of cocaine analogues in perfused livers, as well as to reveal early changes in energy metabolism. The results of these experiments should provide new information about effects of cocaine on liver function and circulating neurohormone levels. They should also provide a basis for understanding the nature of the liver damage that is encountered in some human addicts.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Pharmacology I Research Subcommittee (DABR)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Tufts University
Schools of Medicine
United States
Zip Code
LeDuc, B W; Sinclair, P R; Walton, H S et al. (1994) Cocaine toxicity in cultured chicken hepatocytes: role of cytochrome P450. Toxicol Appl Pharmacol 125:322-32
LeDuc, B W; Sinclair, P R; Shuster, L et al. (1993) Norcocaine and N-hydroxynorcocaine formation in human liver microsomes: role of cytochrome P-450 3A4. Pharmacology 46:294-300
Powers, J F; Alroy, J; Shuster, L (1992) Hepatic morphologic and biochemical changes induced by subacute cocaine administration in mice. Toxicol Pathol 20:61-70
Kanel, G C; Cassidy, W; Shuster, L et al. (1990) Cocaine-induced liver cell injury: comparison of morphological features in man and in experimental models. Hepatology 11:646-51
Engelking, L R; Anwer, M S; McConnell, J et al. (1990) Cocaine and lidocaine interfere with epinephrine-induced changes in intracellular calcium concentration and glucose efflux from rat hepatocytes. Pharmacology 40:129-36
Garhart, C A; Anwer, M S; Shuster, L (1989) Cocaine-induced changes in perfusion pressure and bile flow in perfused rat livers. Biochem Pharmacol 38:2139-45
Shuster, L; Garhart, C A; Powers, J et al. (1988) Hepatotoxicity of cocaine. NIDA Res Monogr 88:250-75
Shuster, L (1986) Genetic markers of drug abuse in mouse models. NIDA Res Monogr 66:71-85
Charkoudian, J C; Shuster, L (1985) Electrochemistry of norcocaine nitroxide and related compounds: implications for cocaine hepatotoxicity. Biochem Biophys Res Commun 130:1044-51