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), Vol. 86:2; Conference: 28 annual Radiation Research Society meeting, New Orleans, LA, USA, 1-5 Jun 1980
- 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
MISONIDAZOLE
RADIOSENSITIVITY EFFECTS
NITRO COMPOUNDS
BIOLOGICAL EFFECTS
REDUCTION
OXYGEN
THIOLS
VITAMIN A
AFFINITY
ASCITES TUMOR CELLS
ASCORBIC ACID
CYANIDES
CYTOCHROMES
DNA
ELECTRON TRANSFER
FIBROBLASTS
GLUCOSE
POTASSIUM COMPOUNDS
RADICALS
REDOX POTENTIAL
STRAND BREAKS
ALDEHYDES
ALKALI METAL COMPOUNDS
ANIMAL CELLS
ANTINEOPLASTIC DRUGS
AZOLES
CARBOHYDRATES
CHEMICAL REACTIONS
CONNECTIVE TISSUE CELLS
DRUGS
ELEMENTS
HETEROCYCLIC COMPOUNDS
HEXOSES
IMIDAZOLES
MONOSACCHARIDES
NONMETALS
NUCLEIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANIC SULFUR COMPOUNDS
PIGMENTS
RADIOSENSITIZERS
SACCHARIDES
SOMATIC CELLS
TUMOR CELLS
VITAMINS
560121* - Radiation Effects on Cells- External Source- (-1987)
560301 - Chemicals Metabolism & Toxicology- Cells- (-1987)