Biomaterial Database

Contrasting molecular cytotoxic mechanisms of mitomycin C and its two analogs, BMY 25282 and BMY 25067, in isolated rat hepatocytes. 1993

J M Silva, and S Khan, and P J O'Brien

Faculty of Pharmacy, University of Toronto, Ontario, Canada.

The molecular cytotoxic mechanisms of mitomycin C (MMC) and its analogs, BMY 25282 and BMY 25067, have been investigated using isolated hepatocytes as a model system for studying toxicity to nondividing tissues. These drugs have quinone and aziridine moieties, and tumor cell cytotoxicity has been attributed to DNA alkylation and cross-linking. By contrast, the following results suggest that these drugs cause oxidative stress in nondividing cells by different mechanisms. Both hepatocytes or hepatic microsomes and NADPH were able to catalyse oxygen activation by all three drugs, suggesting that enzymatic reduction results in the formation of auto-oxidizable species. Their relative effectiveness at activating oxygen was BMY 25282 >> BMY 25067 > MMC. However, their relative cytotoxic effectiveness was BMY 25067 >> BMY 25282 > MMC, and it was increased markedly if hepatocyte glutathione-reductase or catalase was inactivated. Furthermore, ascorbate increased the toxic potencies of both BMY 25282 and MMC in catalase-inactivated hepatocytes by as much as 60- and 40-fold, respectively. Hepatocyte glutathione (GSH) oxidation was also increased. The relative resistance of normal hepatocytes to MMC and BMY 25282 can be attributed therefore, to the high levels of enzymes in hepatocytes involved in hydrogen peroxide detoxification. BMY 25067 cytotoxicity unlike that of BMY 25282 or MMC was prevented by the addition of the thiol reductant dithiothreitol. BMY 25067 also differed in being much more toxic towards GSH-depleted hepatocytes. Furthermore, BMY 25067, unlike MMC and BMY 25282, caused a rapid decrease in hepatocyte ATP levels and inhibited mitochondrial respiration. This could be prevented by the addition of the thiol reductant dithiothreitol, which restored intracellular GSH levels. Its toxic potency to catalase- or glutathione reductase-inactivated hepatocytes also was not increased by ascorbate. Therefore, the cytotoxicity of BMY 25067 can probably be attributed to oxidative stress by the aminodisulfide moiety which causes GSH and mixed disulfide formation, resulting in mitochondrial toxicity.

UI	MeSH Term	Description	Entries
D008099	Liver	A large lobed glandular organ in the abdomen of vertebrates that is responsible for detoxification, metabolism, synthesis and storage of various substances.	Livers
D008297	Male		Males
D008937	Mitomycins	A group of methylazirinopyrroloindolediones obtained from certain Streptomyces strains. They are very toxic antibiotics used as ANTINEOPLASTIC AGENTS in some solid tumors. PORFIROMYCIN and MITOMYCIN are the most useful members of the group.
D010084	Oxidation-Reduction	A chemical reaction in which an electron is transferred from one molecule to another. The electron-donating molecule is the reducing agent or reductant; the electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471).	Redox,Oxidation Reduction
D010101	Oxygen Consumption	The rate at which oxygen is used by a tissue; microliters of oxygen STPD used per milligram of tissue per hour; the rate at which oxygen enters the blood from alveolar gas, equal in the steady state to the consumption of oxygen by tissue metabolism throughout the body. (Stedman, 25th ed, p346)	Consumption, Oxygen,Consumptions, Oxygen,Oxygen Consumptions
D002478	Cells, Cultured	Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.	Cultured Cells,Cell, Cultured,Cultured Cell
D004229	Dithiothreitol	A reagent commonly used in biochemical studies as a protective agent to prevent the oxidation of SH (thiol) groups and for reducing disulphides to dithiols.	Cleland Reagent,Cleland's Reagent,Sputolysin,Clelands Reagent,Reagent, Cleland,Reagent, Cleland's
D005978	Glutathione	A tripeptide with many roles in cells. It conjugates to drugs to make them more soluble for excretion, is a cofactor for some enzymes, is involved in protein disulfide bond rearrangement and reduces peroxides.	Reduced Glutathione,gamma-L-Glu-L-Cys-Gly,gamma-L-Glutamyl-L-Cysteinylglycine,Glutathione, Reduced,gamma L Glu L Cys Gly,gamma L Glutamyl L Cysteinylglycine
D000255	Adenosine Triphosphate	An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate is a neurotransmitter.	ATP,Adenosine Triphosphate, Calcium Salt,Adenosine Triphosphate, Chromium Salt,Adenosine Triphosphate, Magnesium Salt,Adenosine Triphosphate, Manganese Salt,Adenylpyrophosphate,CaATP,CrATP,Manganese Adenosine Triphosphate,MgATP,MnATP,ATP-MgCl2,Adenosine Triphosphate, Chromium Ammonium Salt,Adenosine Triphosphate, Magnesium Chloride,Atriphos,Chromium Adenosine Triphosphate,Cr(H2O)4 ATP,Magnesium Adenosine Triphosphate,Striadyne,ATP MgCl2
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia