ALTERED ENZYME-ACTIVITIES OF XENOBIOTIC BIOTRANSFORMATION IN KIDNEYS AFTER SUBCHRONIC ADMINISTRATION OF CHLORO-4-(DICHLOROMETHYL)-5-HYDROXY-2(5H)-FURANONE (MX) TO RATS

Activities of the xenobiotic metabolizing enzymes were measured in the liver, kidney, duodenum and lung microsomes and cytosol fractions of Wistar rats after subchronic administration of chloro-4-(dichloromethy l)-5-hydroxy-2(5H)-furanone (MX), a potent bacterial mutagen in chlori nated drinking water. MX was administered by gavage at the dose level of 30 mg/kg for 18 weeks (low dose), or at the dose level which was ra ised gradually from 45 mg/kg for 7 weeks via 60 mg/kg for 2 weeks to a clearly toxic dose of 75 mg/kg for 5 weeks (high dose). Microsomal an d cytosolic preparations were made and the activities of 7-ethoxyresor ufin-O-deethylase (EROD), pentoxyresorufin-O-dealkylase (PROD), NADPH- cytochrome-c-reductase, UDP-glucuronosyltransferase (UDPGT) and glutat hione-S-transferase (GST) were measured, Kidneys were affected most. A dose-dependent decrease was observed in EROD (90% in males, 80% in fe males at the high dose) and in PROD (58% in females, at the high dose) in kidneys. An increase was, however, detected in kidney NADPH-cytoch rome-c-reductase (66% in females at high dose), UDPGT (89% in males an d 97% in females at high dose) and GST activities (56% in males and 50 % in females at high dose). MX caused only a few changes in the enzyme activities of the liver. The EROD activity was decreased 25% to 37%, both in the livers of males and females, but the total content of P450 s was not altered. Hepatic GST activity was elevated in females in a d ose-dependent manner (31% and 44%). GST activity was elevated in duode num in females (59%) at the high dose. There were no marked changes in the enzyme activities in the lungs. MX was a weak inhibitor of EROD a ctivity both in the liver and kidney microsomes in vitro, decreasing t he EROD activity by 53% and 43%, respectively at the concentration of 0.9 mM. The results indicate that MX decreases the activity of phase I metabolism enzymes, but induces phase II conjugation enzyme activitie s, particularly in kidneys in vivo. It is possible that these changes contribute;to metabolism of MX in kidneys and renders them susceptible to MX in the course of repeated exposure.