THE STUDY OF GENOTOXICITY OF TWO NEWLY SYNTHESIZED PYRROLINONE DERIVATIVES ON L5178Y MOUSE LYMPHOMA AND BONE MARROW CELLS
A.K. Nersesyan1, G.S. Melikyan2, H. Stopper3
1Cancer Research Centre, Yerevan 52, Armenia 2State University, Yerevan 25, Armenia 3Institute of Pharmacology and Toxicology, Wuerzburg 97078, Germany
Abstract. Genotoxic activity of two newly synthesized pyrrolinone derivatives (lactone (PTB) and lactame (PTP)) was studied both in vitro and in vivo. The substances were incubated with L5178Y mouse lymphoma cells for 4 h, then washed from the substances, and incubated for 18 h. PTP induced significantly increased number of micronuclei (MN) only at the highest dose used (1000 µg/ml). The 20-fold increase of the concentration of PTP led to 2.4-fold increase of the number of MN. PTP wasn’t toxic for lymphoma cells in the applied concentration range. In contrast, PTB induced significantly increased number of MN in lymphoma cells beginning from the concentration of 50 µg/ml and was toxic for lymphoma cells at concentrations of 500 µg/ml and higher. In the comet assay with L5178Y mouse lymphoma cells both substances were active at all concentrations used (PTP at concentrations of 50 µg/ml and 100 µg/ml, and PTB at concentrations of 100 µg/ml and 250 µg/ml). Acute toxicity and MN-inducing activity of compounds were studied on Swiss albino mice. PTB was substantially more toxic for mice than PTP (LD50 was 200 mg/kg and 370 mg/kg respectively). In mouse bone marrow polychromatic erythrocytes PTP induced significantly increased number of MN only at a dose equal to 1/2 of LD50. In contrast, PTB was mutagenic at all doses used — 1/2, 1/5 and 1/10 of LD50. At equitoxic doses PTB induced more than 2-fold and 3.5-fold increased levels of MN compared with PTP (1/2 and 1/5 of LD50 respectively). The replacement of =NH group to =O group in chemical structure of pyrrolinone derivatives leads to substantial increase in acute toxicity for mice (1.85-fold) and MN induction activity both in vivo and in vitro.
Key Words:pyrrolin-2-one derivatives, micronuclei, the comet assay, L5178Y mouse lymphoma cells, mouse bone marrow cells.
