There is growing concern about chronic exposure of operating room personnel and acute exposure of patients to inhalation anesthetics. Recent epidemiological and long-term rat testing data have implicated the inhalation anesthetics in a variety of toxic reactions including liver necrosis, cancer, teratogenicity, and bone marrow defects. Many anesthetics have structural similarities to known toxic compounds such as vinyl chloride and 1, 2-dichloro-2-bromopropane. We have chosen to study halothane as a representative of the halogenated hydrocarbon inhalation anesthetics because of our previous experience with its urinary, volatile, and cellular-bound metabolites. In our previous studies we have demonstrated that human metabolism of halothane is different from that in rats and monkeys. Therefore, we propose to study metabolism in humans directly. We have developed the methodology to purify human cytochromes P-450 to homegeneity and to reconstitute these cytochromes P-450 along with human cytochrome P-450 NADPH-reductase into a phospholipid vesicle system that is capable of carrying out metabolism like that in liver chromosomes. Because of the well-defined nature of this system, we will be able to define exact pathways of anesthetic metabolism as well as to differentiate the pathways dictated by the various cytochromes P-450 produced by several enzyme-inducing agents. We will use this human liver preparation to study production of volatile metabolites as well as binding of highly reactive intermediates to proteins and phospholipids of the liver cell. Studies in rats have associated production of toxic metabolites and liver necrosis with pretreatment by certain enzyme-inducing drugs followed by metabolism of anesthetics under anaerobic conditions. We will attempt to correlate toxicity in animals and humans with specific metabolic pathways occurring in the liver. A goal will be to define those conditions to which patients and operating room personnel should not be subjected in order to prevent significant toxic metabolism.
| Costa, A K; Baker, M A; Brown, J M et al. (1989) In vitro hepatotoxicity of SR 4233 (3-amino-1,2,4-benzotriazine-1,4-dioxide), a hypoxic cytotoxin and potential antitumor agent. Cancer Res 49:925-9 |
