Halo thane

Eliasson, E. and Kenna, J.G., Cytochrome P450 2E1 is a cell surface autoantigen in halo-thane hepatitis, Mol. Pharmacol., 50, 573, 1996. 

In the preceding eqnation, the primary anion-radical gives the l-chloro-2,2,2-trifluoroethyl radical. In vivo, this radical was detected by the spin-trapping method (Poyer et al. 1981). Ahr et al. (1982) had presented additional evidence for the formation of the radical as an intermediate in halo-thane metabolism and identified l-chloro-2,2-difluoroethene as a product of radical stabilization. Metabolytic transformations of l-chloro-2,2-difluoroethene lead to acyl halides, which are relevant to halothane biotoxicity (Guengerich and Macdonald 1993). 

For example, carbon tetrachloride and halo thane are both reduced in this way (see chap. 7). 

Oxygen is normally readily available to all reasonably well-perfused tissues, but deep inside organs such as the liver, especially the centrilobular area (see chap. 6), there will be a reduction in the oxygen concentration. This is clearly important when both oxidative and reductive pathways are available for a particular substrate. Therefore, as conditions in a particular tissue become more anaerobic, reductive pathways will become more important. This is well illustrated by the metabolism of halo thane where, in the rat, hypoxia will increase reductive metabolism and hepa to toxicity (see chap. 7). Glutathione is an extremely important cofactor, involved in both protection and conjugation. It may be depleted by both of these processes, or under certain circumstances, such as hereditary glucose-6-phosphate deficiency in man, supply may be reduced (see chap. 5). This will clearly influence toxicity, and there are a number of examples discussed in chapter 7 in which it is important. 

Of course, the stress proteins themselves may be targets for reactive metabolites or ROS, in which case the protective ability may be lost. For example, a reactive metabolite(s) of halo thane, the hepatotoxic anesthetic drug (see chap. 7), binds to hsp60 and hsp70, which are mainly mitochondrial proteins. 

Briefly describe the important aspects of mechanisms underlying the hepatotoxic effects of the anesthetic drug halo thane. 

Bourdi M, Amouzadeh HR, Rushmore TH, et al. Halo thane induced liver injury in outbred guinea pigs role of trifluoroacetylated protein adducts in animal susceptibility. Chem Res Toxicol 2001 14 362-370. 

In addition to MAK values, which are for healthy persons capable of earning a normal living, the DFG publication20 includes so-called BAT values (biological tolerance limits) for substances which show additional biological effects. These define maximum concentrations of a substance, or its metabolites, normally in the blood or urine of an employee. Only one fluorinated chemical was included in 1997. 2-bromo-2-chloro-l,l,l-trifluoroethane = Halo-thane, CAS-No. 151-67-7, with a BAT value for trifluoroacetic acid (its toxic metabolite) of 25 mg - L 1 in human blood determined after exposure/shift. 

Male Wistar rats (280—320 g of weight) were deeply anaesthetized with halo-thane and subsequendy decapitated. Brain slices were prepared according to a previously described procedure (Geracitano et al., 2003). Briefly, the brain was rapidly removed and corticostriatal coronal slices (300 /nn) were cut from a tissue block with the use of a vibratome (at 20-25 °C) in artificial cerebrospinal fluid solution (ACSF). 

The effect of halo thane (CF3CHBrCl) on the lateral surface conductance and membrane hydration has been studied by Yoshida and coworkers [41]. Below the pretransition temperature, the activation energy of the ion movement (H30++0FT) was 18.1 kj/mol, which corresponds to that of the spin-lattice relaxation time of water (18kJ/mol) above pretransition the activation energy increased to 51.3 kj/mol. Halothane did not show any effect on the ion movement when the temperature was below the pretransition temperature. When the temperature exceeded the pretransition temperature, the authors observed at 0.35 mM halothane (equilibrium concen-... 

Gregory GA, Eger El II, Munson ES (1969) The relationship between age and halo-thane requirement in man. Anaesthesiology, 30 488-491. 

SCHEME 11.18 The metabolism of carbon tetrachloride is characterized by the formation of free radicals. Halo thane and methoxyflurane are sinailarly metabolized. 

Vergani D, Mieli-Vergani G, Alberti A, Neuberger J, Eddleston ALWF, Davis M et al. Antibodies to the surface of halothane-altered rabbit hepatocytes in patients with severe halo thane-associated hepatitis. N Engl J Med 1980 303 66-71. 

Satoh H, Fukuda Y, Anderson DK, Ferrans VJ, Gillette JR, Pohl LR. Immunological studies on the mechanism of halo thane-induced hepatotox-icity Immunohistochemical evidence of trifluo-roacetylated hepatocytes. J Pharmacol Exp Ther 1985 233 857-62. 

Certain halogenated hydrocarbons such as halo-thane, undergo reductive dehalogenation. 

Kalow (2) published a gas phase spectrum of halo-thane in the 7 to 16 micron region. Kakac and Hudlicky (3) published the spectrum of a carbon tetrachloride solution of halothane in the 1600 to 450 cm. region. 

The first reported method of analysis for halo-thane in blood was by turbidimetric measurement. Halo-thane was extracted from blood with petroleum ether. 

Several other cases of hepatitis resulting from occupational exposure to halo-thane have been reported. Thus, there is little doubt that hepatitis may follow the inhalation of this anaesthetic. Extensive surveys of post-operative jaundice have also been carried out. A summary of the findings will be given here. Despite numerous reports in the literature of liver damage in patients who had halothane anaesthesia, there is still considerable controversy between anaesthetists and pathologists as to whether the hepatitis and halothane are causally related. 

Spracklin DK, Hankins DC, Fisher JM, Thummel KE, Kharaseh ED (1997) Cytoehrome P450 2Elis the prineipal eatalyst of human oxidative halo-thane metabolism in vitro. J Pharmaeol Exp Ther 281 400 11... 

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