Sitaram S. Pawar

Riboflavin and drug metabolism in adult male and female rats

Abstract Oxidative metabolism of drugs in vitro in liver 9000 g supernatant fraction from riboflavin-deficient adult male and female rats was investigated. A significant decrease in overall oxidation of aminopyrine, ethylmorphine, N-methylaniline, aniline and acetanilide was observed. Studies at two deficiency levels indicate that a marked decrease in specific activities of N-demethylation of aminopyrine. ethylmorphine. N-methylaniline and hydroxylation of aniline and acetanilide occurs in both male and female rats. The levels of drugmetabolizing enzymes were further lowered with increase in deficiency. The levels of flavin, NADPH cytochrome c reductase, cytochrome P-450 and cytochrome b5 were reduced in riboflavin-deficient (7 weeks) male rats as compared to normal rats. The activity of drug enzymes from riboflavin-deficient rats was stimulated by pretreatment with phenobarbital. A significant reversal of drug enzyme activities was noted when riboflavin was administered to deficient animals.

In vivo and in vitro effects of caffeine on hepatic-mixed function oxidases in rodents and chicks

Administration of caffeine, ip 100 mg/kg/day for 1-5 days, to adult male rats resulted in a significant increase in hepatic cytochrome P-450 and b5 concentrations and in cytochrome c reductase, aminopyrine N-demethylase and acetanilide hydroxylase activities. No change was seen in relative liver weight but microsomal protein content was increased after treatment for 1 day and decreased after treatment for 3 or 5 days. In adult rats given 25, 100 or 150 mg caffeine/kg for 3 days, maximum stimulation of mixed-function oxidases was seen with the 100-mg/kg dose. Caffeine treatment (100 mg/kg for 3 days) increased relative liver weight in female guinea-pigs and decreased it in chicks and female mice, and decreased microsomal protein content in male mice, female guinea-pigs and young rats, and increased it in chicks. A significant increase in hepatic cytochrome P-450 content was seen in all species studied. Cytochrome b5 content was increased in chicks and young rats, while cytochrome c reductase activity was increased in male and female mice, young rats and chicks and decreased in female guinea-pigs. Aminopyrine N-demethylase activity was increased in young rats and female guinea-pigs, and acetanilide hydroxylase was increased in all test species except male mice. In vitro addition of 2.5 mM-caffeine to microsomal incubations from untreated rats, guinea-pigs, mice and chicks inhibited aminopyrine N-demethylase activity, although only to a significant extent in male mice; addition of caffeine to incubations containing microsomes from caffeine-treated animals produced significant inhibition of aminopyrine N-demethylase activity in microsomes from adult and young rats and female guinea-pigs. Aminopyrine N-demethylase inhibition did not increase with increasing concentration of added caffeine, although acetanilide hydroxylase activity was progressively inhibited in the microsomal incubates from both control and caffeine-treated animals.

Effect of caffeine on the hepatic microsomal mixed function oxidase system during phenobarbital and benzo[a] pyrene treatment in rats

Simultaneous administration of caffeine (100 mg/kg, i.p., 3 days) and phenobarbital (80 mg/kg, i.p., 3 days) to adult male rats resulted in a significant decrease in hepatic cytochrome P-450 and acetanilide hydroxylase activity, compared to phenobarbital administration alone. While simultaneous administration of caffeine and benzo[a]pyrene (20 mg/kg, i.p., 2 days) increased acetanilide hydroxylase, compared to benzo[a]pyrene administration, no change was seen in the cytochrome P-450 concentration. In vitro addition of 2.5 mM caffeine to microsomal incubations from untreated, phenobarbital- and benzo[a]pyrene-treated rats inhibited aminopyrine N-demethylase activity. No significant difference was seen in the extent of aminopyrine N-demethylase inhibition due to the in vitro addition of caffeine to microsomes from untreated or phenobarbital-treated rats, whereas inhibition in microsomes from benzo[a]pyrene-treated rats was greater.

Hepatic aminopyrine n-demethylase, acetanilide hydroxylase and lipid peroxidation in young growing rats during the treatment of insecticides

Halogenated hydrocarbon insecticides and their metabolites are knovm to alter the activity of microsomal enzymes(HART et a1.1963, HART and FOUTS 1963, 1965, WELCH et a1.1967, BUNYAn and PAGE 1973). in contrast to the halogenated hydrocarbons there are very few reports regarding the effect of organophosphorus and carbamate insecticides on microsomal drug metabolizing enzymes. Hepatic drug metabolism has been found to be decreased by malathion in mice and rats (STEVENS et al. 1972, RA0 and ANDERS 1973, STEVENS and GREENE 1973). Very recently, STEVENS and GREENE (1974) have showed that subacute administration of insecticides resulted in induction of hepatic drug metabolism and mixed function oxidase systems in rats! however, WEBER et a1,(1974) have reoorted that parathion inhibited the metabolism of benzo(a)pyrene in rat liver and intestine. Our earlier investigations have reported an increase in drug metabolizing enzymes and lipid peroxidation during Take20 administration and a decrease in drug metabolism followed by an increased lipid peroxidation during Baygon administration in young growing rats (MAKHIJA and PAWAR 1974,1975). A literature review indicates a paucity of toxicological data and hence the present experiments were planned to investigate the effect of Take-20 (0,0dimethyl malathion) and Baygon on hepatic drug metabolism and lipid peroxidation in young growing rats.

Effect of ampicillin on hepatic microsomal mixed-function oxidase system in male mice

The effect of ampicillin [(D)-alpha-aminobenzyl penicillin] administration on the hepatic mixed-function oxidase (MFO) system was studied in male mice. Ampicillin (100 mg/kg, i.p., 3 days) decreased the levels of cytochrome P-450, aminopyrine N-demethylase, acetanilide hydroxylase and cytochrome c-reductase activity significantly. In carbon tetrachloride (CCl4)-pretreated mice, ampicillin increased acetanilide hydroxylation compared with CCl4 treatment alone; however, all other parameters of the MFO system remained unchanged. Ampicillin exhibited type II binding with microsomes (trough at 388 nm, peak at 430 nm). Thus ampicillin acts as an inhibitor of the MFO system.

Alterations in hepatic drug metabolism and lipid peroxidation during administration of Baygon, a pesticide

Biochemical studies during low- and high-dose administration of Baygon (a pesticide) to young male rats were performed. It was observed that the activities of drug-metabolizing enzymes were decreased even at a low dose of Baygon and the decrease was much more significant during high-dose injections. Lipid peroxidation was increased with a low dose and the increase was much more pronounced with a high dose. Besides these changes the animals showed physical changes such as salivation, fasciculations, etc. The presence of conjugated diene absorption patterns and malonaldehyde formation indicated the in vivo lipid peroxidation dut to Baygon administration. Toxic effects leading to death were noted when the animals were injected with a high dose of the pesticide, Baygon above 25 mg/kg.

The toxicity of endrin and the effect of pretreatment of phenobarbital and hexobarbital on mortality in four fresh water fishes.

A considerable degree of contamination of agricultural products and mans environment occurs due to the wide use of insecticides in controlling various types of insects and pests on farms. Endrin (l,2,3,4,10,10-Hexachloro-6,7-epoxy-l,4,4a,5,6, 7,8,8a octahydro-endo-endo-l,4;5,8-dimethanonaphthalene) and its metabolites may enter the aquatic ceosystem by runoff. These may create problems for inland fishery if they prove lethal and for toxicologists if sublethal doses are consumed by the fishes or its feed because these chlorinated hydrocarbons have a tendency towards getting deposited in the fish body (ALLISON et al. 1964; BURDICK et al. 1964).

TOXICITY OF 2-CHLOROBENZYLIDENE MALONONITRILE AND HEPATIC MICROSOMAL MIXED FUNCTION OXIDASE SYSTEM

Publisher Summary This chapter discusses the toxicity of 2–chlorobenzylidene malononitrile (2–ClBMN) and hepatic microsomal mixed function oxidase system. 2–Chlorobenzylidene malononitrile is the active ingredient of a wide range of materials used against civil disturbances and in war. It interacts locally with receptors of sensory nerves in skin and mucosae causing uncomfortable sensations at the contaminated area with reflex effects. Study of acute inhalation toxicity of 2–ClBMN generated in the form of pyro-technique smoke has been reported. 2–ClBMN releases its active metabolites such as cyanide and benzaldehyde into the body and manifests its toxic effects at various levels. This chapter describes the interactions of mixed function oxidase system (MFOS) with 2–ClBMN and its metabolites. Studies on toxicity of 2–ClBMN and MFOS show that 2–ClBMN and benzaldehyde impair cytochrome P-450 structure and function, probably irreversibly. However, the microsomal protein level remains unaltered. Cyanide acts on MFOS directly, and sodium thiosulphate and sodium nitrite release MFOS from the effects of cyanide by interactions of cyanide with antagonists and subsequent removal from the site of reaction.