Effects of bleomycin on liver antioxidant enzymes and the electron transport system from ad libitum-fed and dietary-restricted female and male Fischer 344 rats

Abstract

Dietary restriction (DR) is the only known intervention that delays aging and age-related diseases. Mechanisms proposed to explain this DR effect include a decline in free radical production and an increase in free radical detoxification. In the present study the effect of bleomycin (BLM) as a reactive oxygen species-generating antitumor drug has been evaluated on antioxidant enzymes and the electron transport system in different cellular fractions of liver in female and male Fischer 344 rats. Animals were fed ad libitum (AL) or 60% of the AL intake (DR) and were given a single intraperitoneal injection of 2.5, 5, or 10 mg BLM/kg body wt. After four weeks, BLM significantly increased glutathione peroxidase and lactate dehydrogenase activities in liver cytosol of female AL rats and increased activity even more in male rats. Similar changes were also noted for glutathione reductase and glucose 6-phosphate dehydrogenase activities in BLM-treated AL rats. In liver mitochondria, glutathione peroxidase was increased in female and male AL rats but was increased more in female rats. Drug treatment had no significant effect on these enzyme activities in cytosolic or mitochondrial fractions of DR animals. Profound effects of BLM were noted in activities of complexes I, III, and IV of the electron transport system in AL and DR female and male rats; however, complex II demonstrated no significant diet or treatment effect. Induced antioxidant enzyme activities in BLM-treated AL rats may be a response to excessive free radical generation due to BLM metabolism in AL animals that is mitigated by DR. Furthermore, dysfunction of the electron transport system might suggest its role in a secondary generation of free radicals during BLM metabolism contributing to its toxicity.