EFFECT OF HEAVY METAL TOXICANTS ON LIVER FUNCTION AND HEPATIC DRUG METABOLIZING ENZYME SYSTEM IN RABBIT

Toxic effects of cadmium had been studied on the liver function and drug metabolizing enzymes of male New Zealand white rabbits, oryctolagus cuniculus with and without pretreatment with phenobarbitone and promethazine. Aqueous solution of cadmium chloride (CdClz) injected intraperitoneally according to the following schedule.\ud \ud 1A group of 3 rabbits injected with aqueous CdClz solution at a dose of 6 mg/kg body weight per day for 5 days.\ud \ud 2A group of 3 rabbits injected with aqueous solution phenobarbitone at a dose of 5 mg/kg body weight pre day for 5 days.\ud \ud 3A group of 3 rabbits injected with aqueous solution promethazine at a dose of 5 mg/kg body weight pre day for 5 days.\ud \ud 4A group of 3 rabbits injected with aqueous solution phenobarbitone at a dose of 5 mg/kg body weight pre day for 5 days followed by CdClz at a dose of 6 mg/kg body weight per day for another 5 days.\ud \ud 5A group of 3 rabbits injected with aqueous solution promethazine at a dose of 5 mg/kg body weight pre day for 5 days followed by CdClz at a dose of 6 mg/kg body weight per day for another 5 days.\ud \ud At the end of stipulated period, the blood sera were analysed for the estimation of activities of alkaline phosphatase (AP), glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), isocitrate dehydrogenase (ICDH) and lactate dehydrogenase (LDH).\ud \ud Livers were processed for the estimation of soluble hepatic enzymes like AP, GOT, GPT, ICDH and LDH and microsomal enzymes.\ud \ud Hepatic microsomes were prepared and used for the estimation of several drug metabolizing enzymes like cytochrome P-450, aniline hydroxylase, acetanilide hydroxylase, benzphetamine demethylase, aminopyrine demethylase, N.N. dimethyl aniline demethylase, cytochrome b5, cytochrome-c-reductase and N.N. dimethyl aniline N-oxide.\ud \ud The various effects of cadmium chloride and drugs pretreatments are summarized below.\ud \ud Effects of phenobarbitone\ud \ud 1 Phenobarbitone treatment produced significant decrease (68%) in body weight gain while relative liver weight was not affected.\ud \ud 2Serum GOT, GPT, LDH and ICDH were inhibited 21%, 69%, 25% and 35% respectively. Activity of AP activity increased 64%.\ud \ud 3GPT and AP decreased 47% and 48%, respectively while activities of hepatic LDH and ICDH were increased 919% and 111%, respectively. Hepatic GOT remained unaffected.\ud \ud 4Activities of drug metabolizing enzymes like cytochrome P- 450 (194%), aniline hydrosylase (271%), acetanilide bydroxylase (162%), benzphetamine demethylase (112%), amino pyrine demethylase (87%), N.N. dimethyl aniline demethylase (81%) were increased. Activity of aniline N-oxide was also increased 100% Cytochrome b5 and cytochrome-c-reductase were inhibited 73% and 48%.\ud \ud Effect of promethazine\ud \ud 1Promethazine administration produced decrease in body weight gain while there was no change in liver weight.\ud \ud 2The serum GPT activity was inhibited 73% while LDH activity was increased 36%. Serum GOT, ICDH and AP activities remained unaffected.\ud \ud 3The hepatic GPT and AP activities were decreased 50% and 42%, respectively. LDH and ICDH activities were increased 156% and 41%, respectively. However, hepatic GOT activity remained unaffected.\ud \ud 4There was no effect on any of studied drug metabolizing enzymes except for aniline hydroxylase and acetanilide hydroxylase, which increased 58% and 56%, respectively.\ud \ud Effect of cadmium chloride\ud \ud 1The total body weight under all conditions of cadmium chloride administration decreased significantly while relative liver weight remained unaffected.\ud \ud 2Serum GOT and LDH activities increased 89% and 86% respectively, while of GPT, AP and ICDH were inhibited 83%, 63% and 17% respectively.\ud \ud In the phenobarbitone pretreated rabbits administration of cadmium chloride increased the activities of serum GOT, LDH and ICDH 49%, 73% and 32%, respectively. Activity of AP was decreased 69%.\ud \ud In promethazine pretreated rabbits cadmium chloride administration decreased the activities of serum GOT, GPT, LDH and AP, 56%, 35%, 27% and 25%.\ud \ud 3The hepatic GOT increased 160%. Activities of hepatic GPT and AP were decreased 37% and 75% after cadmium treatment.\ud \ud In phenobarbitone pretreated rabbits, hepatic GOT activity was increased 378% while LDH and ICDH were decreased 70.and 41% respectively after cadmium treatment.\ud \ud The promethazine pretreated rabbits, GOT was increased 219%. Activities of LDH and AP were decreased 475 and 33%, respectively after cadmium treatment.\ud \ud 4Most of the drug metabolizing enzymes were inhibited. Cytochrome P-450 and its isoenzymes, aniline hydroxylase, acetanilide hydroxylase, benzphetamine demethylase, aminopyrine demethylase, N.N. dimethyl aniline demethylase were inhibited 41%, 31%, 40%, 695, 78% and 855, respectively. N.N. dimethyl aniline N. oxide formation was inhibited 86%. Cytochrome b5 and cytochrome-c-reductase were remained unaffected.\ud \ud When administered to phenobarbitone pretreated rabbits, the activities of cytochrome P-450, aniline hydroxylase acetanilide, hydroxylase, benzphetamine demethylase, aminopyrine demethylase, N.N. dimethyl aniline demethylase were inhibited 59%, 59%, 40%, 74%,68% and 66%, respectively. Cytochrome-c-reductase and cytochrome b5 increased 14% and 824%, respectively. N.N. dimethyl aniline N-oxide was inhibited 27%.\ud \ud When administered to promehtazine pretreated animals, N.N. dimethyl aniline demethylase, benzphetamine demethylase and aminopyrine demethylase were inhibited 21%, 16% and 19%, respectively. Activity of acetanilide hydroxylase increased 114%. Rest of the drug metabolizing enzymes remained unaffected by the cadmium chloride treatment