Cellular electron transfer and radical mechanisms for drug metabolism
Aerobic and anaerobic reductions of various nitroaromatic compounds by mammalian cells result in the production of reactive intermediates. Drug reduction is dependent upon glucose, nonprotein thiols, endogenous enzyme levels, and drug electron affinity. Drugs with electron affinities approaching that of oxygen are reduced, in the presence of oxygen, beyond a one-electron radical anion. Nitroaromatic radical anion inactivation occurs by reaction with cellular ferricytochrome c, endogenous thiols, and with oxygen. In the latter case the reaction results in the production of peroxide. Drugs that are substrates for the enzyme glutathione-S-transferase remove endogeneous thiols and demonstrate peroxide production without prior thiol removal. Less electron affinic drugs such as misonidazole require thiol removal as well as the presence of cyanide or azide for maximal peroxide production. Under anaerobic conditions radical anion and nitroso intermediates are reactive with glutathione. Removal of endogenous thiols by hypoxic preincubation with misonidazole may be related to the enhanced radiation response and cytotoxicity of this drug. Reduction of nitro compounds in the presence of DNA and chemicals such as dithionite, zinc dust, or polarographic techniques causes binding to macromolecules and DNA breaks. Chemical-reduction of nitro compounds by ascorbate in the presence of cells enhances drug cytotoxic effects.
- Research Organization:
- Case Western Reserve Univ., Cleveland, OH
- OSTI ID:
- 6454462
- Journal Information:
- Radiat. Res.; (United States), Journal Name: Radiat. Res.; (United States) Vol. 86:2; ISSN RAREA
- Country of Publication:
- United States
- Language:
- English
Similar Records
3'-Formyl phosphate-ended DNA: high-energy intermediate in antibiotic-induced DNA sugar damage
Role of thiols in cellular response to radiation and drugs. Symposium: thiols
Related Subjects
560301 -- Chemicals Metabolism & Toxicology-- Cells-- (-1987)
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
AFFINITY
ALDEHYDES
ALKALI METAL COMPOUNDS
ANIMAL CELLS
ANTINEOPLASTIC DRUGS
ASCITES TUMOR CELLS
ASCORBIC ACID
AZOLES
BIOLOGICAL EFFECTS
CARBOHYDRATES
CHEMICAL REACTIONS
CONNECTIVE TISSUE CELLS
CYANIDES
CYTOCHROMES
DNA
DRUGS
ELECTRON TRANSFER
ELEMENTS
FIBROBLASTS
GLUCOSE
HETEROCYCLIC COMPOUNDS
HEXOSES
IMIDAZOLES
MISONIDAZOLE
MONOSACCHARIDES
NITRO COMPOUNDS
NONMETALS
NUCLEIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANIC SULFUR COMPOUNDS
OXYGEN
PIGMENTS
POTASSIUM COMPOUNDS
RADICALS
RADIOSENSITIVITY EFFECTS
RADIOSENSITIZERS
REDOX POTENTIAL
REDUCTION
SACCHARIDES
SOMATIC CELLS
STRAND BREAKS
THIOLS
TUMOR CELLS
VITAMIN A
VITAMINS