Peroxisome proliferators are ubiquitous rodent hepatocarcinogens, known to modulate the activities of
xenobiotic-metabolising
enzymes such as
glutathione S-
transferases (GST) and
mixed-function oxidase (cytochrome P-450). In addition these compounds induce pleiotropic changes in the liver of rodents even after a short-term treatment. It has been hypothesised that the enzymatic and cellular changes induced by
peroxisome proliferators may alter the toxicity of other compounds activated by
cytochrome P-450 and detoxified by GST
isoenzymes. The effect of
nafenopin-induced changes in the liver of rats on the toxicity of an anti-
cancer drug cyclophosphamide was studied using cyto- and geno-toxicity parameters in the liver and bone marrow cells. The administration of
cyclophosphamide (10 or 20 mg/kg bw) to the rats pre-treated with 80 mg/kg bw of
nafenopin for 2 days resulted in significantly increased cytotoxic response in bone marrow cells. However, genotoxicity of
cyclophosphamide was increased only in the liver of
nafenopin pre-treated rats. Low level of genotoxicity in bone marrow could be accounted for potentiated cytotoxicity of
cyclophosphamide. These events coincided with a significant, up to 5-fold, increase in indirect activation-detoxication index for
cyclophosphamide, determined as a ratio of ECOD and GST activities, in
nafenopin treated rats. This resulted from the induction of ECOD responsible for the formation of reactive metabolites of
cyclophosphamide and reduced activity of GST responsible for their detoxication. In addition, mitotic activity of hepatocytes was increased in
nafenopin treated rats that might also have an impact on the genotoxicity of
cyclophosphamide in this organ.