Influence of gamma-rays on the mouse liver cytochrome P450 system and its modulation by phenothiazine drugs.
OBJECTIVE
Phenothiazine drugs have been found to sensitize hypoxic cancer cells while offering protection to normal cells. Since phenothiazines are known to induce the cytochrome P450 system, its radiomodulation by phenothiazines has been examined.


METHODS
Mice were administered phenothiazines intraperitoneally and irradiated with different doses of gamma-rays at 1.38 Gy/min. The activities of NADPH-cytochrome P450 reductase and NADH-cytochrome b5 reductase, the content of cytochrome P450 and b5, the extent of lipid peroxidation as well as the activities of LDH, XO, SOD, GST and DTD were determined in the liver.


RESULTS
The levels of different components of the cytochrome P450 system and antioxidant enzymes were enhanced up to 5 Gy and decreased thereafter. However, a progressive increase was noticed in peroxidative damage and the activities of LDH and XO. Administration of phenothiazines enhanced the radiation effect on components of the cytochrome P450 system (except NADH-cytochrome b5 reductase) and the activities of SOD, GST and DTD. Concomitantly, phenothiazines inhibited lipid peroxidation, LDH and XO.


CONCLUSIONS
Activation of the cytochrome P450 system by phenothiazines leading to the enhancement of antioxidant potential of animals and free-radical scavenging are attributes of the radioprotective action of phenothiazines.
Chandra
D
D
Radiation Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.
Kale
R K
RK
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects*; D003579:Cytochrome Reductases / Q000378:metabolism / Q000528:radiation effects; D042966:Cytochrome-B(5) Reductase; D005720:Gamma Rays; D007770:L-Lactate Dehydrogenase / Q000378:metabolism / Q000528:radiation effects; D015227:Lipid Peroxidation / Q000528:radiation effects; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000528:radiation effects*; D008297:Male; D051379:Mice; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism / Q000528:radiation effects; D010084:Oxidation-Reduction / Q000528:radiation effects; D010640:Phenothiazines; D014969:Xanthine Oxidase / Q000378:metabolism / Q000528:radiation effects
D000975:Antioxidants; D014150:Antipsychotic Agents; D010640:Phenothiazines; D003577:Cytochrome P-450 Enzyme System; D007770:L-Lactate Dehydrogenase; D014969:Xanthine Oxidase; D003579:Cytochrome Reductases; D042966:Cytochrome-B(5) Reductase; D009251:NADPH-Ferrihemoprotein Reductase