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Biomedical subjects

B R Brown

Publications and source records attributed to B R Brown.

At least 91 records · Page 5Linked to original sources
PubMed1977

Bioactivation and covalent binding of halothane to liver macromolecules.

In this manuscript we report our attempts to determine if 14C-halothane or its metabolites interact with DNA. Three bioactivation systems were used: in vitro microsomal incubations, isolated hepatocytes, and in vivo administration. Even though we used optimal conditions for bioactivation, no significant covalent binding of 14C to DNA was observed. Slight 14C activity above background (6 dpm/0.1 mg DNA) was observed in the microsomal incubations but is considered insignificant because it was not reduced when NADPH was omitted from the incubations. We are able to demonstrate covalent binding to nuclear lipids and proteins when rats were pretreated with phenobarbital and maintained in a hypoxic environment (14% O2). Similarly, these conditions markedly increased covalent binding of 14C from 14C-halothane to microsomal proteins and lipids. Isolated rat hepatocytes proved to be a viable system for studying the bioactivation of halothane. In this system it was also possible to demonstrate increased binding under N2 and/or phenobarbital pretreatment.

Animals↗
PubMed1977

Halothane hepatotoxicity and the reduced derivative, 1,1,1-trifluoro-2-chloroethane.

Halothane (1,1,1-trifluoro-2-bromo-2-chloroethane) is a safe, clinically useful inhalation anesthetic. Rare, unpredictable cases of liver necrosis have been reported following its use. Although the mechanism of this reaction in man is unknown the most plausible is biotransformation to reactive intermediates compounds. The oxidative metabolism of halothane appears to be benign. There is early evidence that reductive (nonoxygen dependent) may be harmful. Since the bromine atom of halothane appears to possess weak bond energy, the reduced, debrominated derivative of halothane, 1,1,1-trifluoro-2-chloroethane, was synthesized and tested for hepatotoxicity in the rat. The derivative is unstable and thus was prepared anaerobically and trapped in propylene glycol solvent. Injection of small amounts of this compound into the portal vein of rats produces extensive liver necrosis. It is postulated that biotransformation of halothane via a reductive pathway could produce this reactive intermediate metabolite.

Animals↗
PubMed1976

Kinetics of methoxyflurane biotransformation with reference to substrate inhibition.

The kinetics of biotransformation of methoxyflurane by rat hepatic microsomes in vitro was studied. The rate of biotransformation as measured by analysis of metabolites continued to increase even at near-saturation concentrations of the anesthetic. Methoxyflurane biotransformation followed either an unbounded curve with empirical formula y = a ln(bx + 1) or an asymptotic curve with formula (see article) No substrate inhibition was observed. Total fluoride Vmax of 135.1 mmumol F-/mg protein/30' was increased to 931.9 by phenobarbital induction; free fluoride Vmax from 39.2 to 403.2. Thus, enzyme induction shifted biotransformation to the production of greater amounts of inorganic free fluoride metabolites than organic fluoride-containing metabolites. Phenobarbital induction caused qualitative as well as quantitative alteration in the biotransformation of methoxyflurane.

Anesthesia, Inhalation↗
PubMed1976

An animal model of hepatotoxicity associated with halothane anesthesia.

Hepatic necrosis was induced in rats by a single exposure to 1 per cent halothane in oxygen following pretreatment with a single dose of Aroclor 1254, a polychlorinated biphenyl. The hepatic lesion was centrilobular and multifocal, and morphologically similar to that reported to occur in man. In-vitro incubation with 14C-halothane indicated an enhanced covalent binding of halothane metabolites to hepatic microsomal macromolecules, particularly lipids, following Aroclor 1254 pretreatment. Lipoperoxidation of microsomal unsaturated fatty acids was not observed with these animals.

Anesthesia, Inhalation↗
PubMed1976

Clinical significance of the biotransformation of inhalation anesthetics.

Inhalation anesthetics, a class of drugs formerly believed to be biologically inert, are now recognized to undergo considerable biotransformation. The viscerotoxicity of certain anesthetics on kidney and liver can be explained in terms of metabolism. The entity of "halothane hepatitis" remains mechanistically and diagnostically a mystery, but if it exists, it could be due to abnormalities of biotransformation.

Anesthesia, Inhalation↗