Modulation of tricarboxylic acid cycle dehydrogenases during hepatocarcinogenesis induced by hexachlorocyclohexane in mice

The sequential distribution of key tricarboxylic acid (TCA) cycle enzymes have been investigated during hexachlorocyclohexane (HCH)-induced hepatocarcinogenesis in Swiss mice. Animals were continuously exposed to HCH (500 ppm) for 2, 4, and 6 months until liver tumor developed. The activity of TCA cycle enzymes such as isocitrate dehydrogenase (ICDH), succinate dehydrogenase (SDH), and malate dehydrogenase (MDH) have been studied. The activity of all the enzymes declined after 2 months of exposure of HCH in the liver. The neoplastic nodules and tumors developed after an exposure of HCH for 4 and 6 months, respectively. Neoplastic nodule and tumor showed wide variations in the activity and distribution of TCA cycle enzymes. The decreasing pattern in the activity of enzymes persisted in the non-neoplastic and non-tumor regions of the liver except SDH. However, the cells in nodular area and tumor showed intense enzymatic activities at cellular level. In the nodular region SDH activity declined prominently, whereas the non-nodular area showed positive reaction. Conspicuously, the tumor showed islands of positive and negative zones for TCA cycle dehydrogenases. The significance and relevance of such a distribution pattern still remains a mystery. The results are discussed in the light of HCH-induced toxicity on energy metabolism in exposed animals and possible role of such enzymes in the tumor formation.