The objectives of these investigations are to: 1) determine the absolute mechanisms by which halogenated volatile anesthetics produce hepatotoxicity in the two clinically relevant animal models successfully initiated in this laboratory; 2) proceed with ongoing studies of therapeutic agents to ameliorate this toxicity; 3) provide clinical guidelines to reduce the risk of anesthetic hepatotoxicity. Halothane and enflurane, two widely used volatile anesthetics that are known to produce sporadic and spontaneous liver damage, will initially be tested. These agents will be administered to animals under conditions of mild hypoxia or pretreatment with polychlorinated biphenyls, both of which promote the production of toxic metabolites in vivo. A variety of parameters will be tested in the model systems to understand the absolute conditions required for toxicity, such as pretreatment with a variety of agents known to alter biotransformation, various oxygen tensions, species, sex and strain variations, diet, and liver integrity. A multitude of therapeutic agents will be tested in the model systems, including specific biotransformation inhibitors and protective agents. Considerable emphasis will be placed on determining the metabolic pathways for these anesthetics because biotransformation appears to be prerequisite for expression of toxicity. Actual metabolites will be isolated, identified and quantified. Covalent binding of radiolabeled anesthetics to tissue macromolecules will be performed to correlate tissue damage with the production of reactive intermediates. The information from these studies will provide us with clinical guidelines for anesthetic administraiion that will minimize the risk of hepatotoxicity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK016715-18
Application #
3225638
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1979-09-01
Project End
1990-07-31
Budget Start
1989-07-01
Budget End
1990-07-31
Support Year
18
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Arizona
Department
Type
Schools of Medicine
DUNS #
City
Tucson
State
AZ
Country
United States
Zip Code
85722
Ghantous, H; Fernando, J; Gandolfi, A J et al. (1991) Inhibition of protein synthesis and secretion by volatile anesthetics in guinea pig liver slices. Adv Exp Med Biol 283:725-30
Lind, R C; Gandolfi, A J (1991) Covalent binding of oxidative biotransformation reactive intermediates to protein influences halothane-associated hepatotoxicity in guinea pigs. Adv Exp Med Biol 283:763-6
Lind, R C; Gandolfi, A J; Hall, P D (1990) Covalent binding of oxidative biotransformation intermediates is associated with halothane hepatotoxicity in guinea pigs. Anesthesiology 73:1208-13
Ghantous, H N; Fernando, J; Gandolfi, A J et al. (1990) Biotransformation of halothane in guinea pig liver slices. Drug Metab Dispos 18:514-8
Lind, R C; Gandolfi, A J; Hall, P M (1990) Isoniazid potentiation of a guinea pig model of halothane-associated hepatotoxicity. J Appl Toxicol 10:161-5
Lind, R C; Gandolfi, A J; Hall, P D (1989) Age and gender influence halothane-associated hepatotoxicity in strain 13 guinea pigs. Anesthesiology 71:878-84