Swaraj Kaur

Comparative evaluation of stimulatory effects of oral tobacco and nicotine consumption on hepatic microsomal N-demethylations

Abstract The present study was designed to investigate and compare the effects of chronic oral tobacco and nicotine consumption on hepatic microsomal drug metabolizing enzymes (DME) responsible for N-demethylation of amidopyrine, morphine and pethidine in rat. Chronic administration of tobacco for 28 days resulted in a marked increase in the rate of N-demethylation of amidopyrine, morphine and pethidine. Such tobacco treatment stimulated amidopyrine and pethidine N-demethylations about 2.5-fold but that of morphine less than 2-fold. The N-demethylation of these drugs was not affected by tobacco treatment for 2 and 7 days. Attempts were made to evaluate the role of nicotine in stimulation of DME by oral tobacco intake. Tobacco was found to contain 4.3 ± 0.18% nicotine on a dry weight basis. Although the magnitude of elevation in microsomal N-demethylations of these drugs by chronic oral intake of nicotine for 28 days was comparable to that obtained by tobacco treatment, there was marked difference in the substrate specificity in stimulation of amidopyrine and morphine N-demethyl-ations. Nicotine treatment for 2 and 7 days, like tobacco, was also devoid of any influence on the microsomal N-demethylations. Both tobacco and nicotine inhibited in vitro biotransformations of amidopyrine, morphine and pethidine to their demethylated metabolites and the degree of inhibition in the two cases did not differ much when compared for different substrates. Preincubation studies demonstrated that the inhibition of amidopyrine N-demethylation by tobacco increased with time but remained unaffected by nicotine. The nature of inhibition of amidopyrine N-demethylase by tobacco and nicotine was non-competitive and competitive respectively. The activities of hepatic microsomal N-demethylases were unaffected in rats killed after 1 hr of a single oral dose of tobacco or nicotine. Therefore, it may be interpreted that stimulation of DME is possibly due to de novo synthesis of DME.

Stimulation of drug and carcinogen metabolism by prolonged oral tobacco consumption

Oral administration of tobacco to rats for 21 days caused remarkable stimulation of the metabolism of phenacetin, aniline and benzo[a]pyrene, a carcinogen, by hepatic microsomal mixed function oxidases (MFO). Such treatment for 6 days resulted in a small increase in the activities of phenacetin O-dealkylase and aromatic hydrocarbon hydroxylase (AHH) without affecting aniline hydroxylase activity. Nicotine given orally was found to be a relatively weak inducer of phenacetin O-dealkylase and aniline hydroxylase, and elicited a maximum increase in their activities within 6 days which remained unchanged even after 21 days of continuous administration. However, these two enzyme systems were not affected following only one or two doses of tobacco and nicotine. Both tobacco and nicotine inhibited these biotransformations in vitro.

Membrane Stabilization and Inhibition of Lipid Peroxidation by Anti-Inflammatory Indoles

Nine 2-aryl-3-[4-(substituted phenyl)-3-thiosemicarbazone] indoles were evaluated for their ability to protect the human erythrocyte membrane against hypo-osmotic hemolysis and inhibit lipid peroxidation in rat liver homogenate in vitro. All compounds caused membrane stabilization and inhibition of lipid peroxidation when tested at final concentrations of 5 X 10(-4) and 2.5 X 10(-5) mol/l, respectively. These biochemical effects were not related to the anti-inflammatory property exhibited by the compounds.

Selective induction of xenobiotic metabolizing esterases/amidases of liver by methaqualone consumption

The present investigation reports the influence of po and ip methaqualone administration on the hydrolytic metabolism of acetylsalicylic acid, procaine, p-nitrophenylacetate, acetanilid, and butyrylcholine in the liver, kidney, and brain of male rats. Oral administration of methaqualone (60 mg/kg/day) to rats for 20 days caused 41.0, 46.5, and 55.0% stimulation of acetylsalicyclic acid esterase I, acetylsalicyclic acid esterase II, and acetanilid N-deacetylase, respectively, in the liver. Under such conditions, the activities of other esterases remained unaffected. The responses of tissue esterases to ip methaqualone treatment (40 mg/kg/day for 6 days) were similar to those observed after po methaqualone administration. Since a single po dose of methaqualone failed to produce any alteration in the rate of metabolism of acetylsalicylic acid, procaine, p-nitrophenylacetate, acetanilid, and butyrylcholine within 20 hr, it may be interpreted that the stimulation of acetylsalicylic acid and acetanilid metabolism is possibly due to selective enhanced de novo synthesis of the enzymes/isozymes necessary for the hydrolysis of the two drugs. The ability of the kidney and brain to metabolize the esters/amides was not modified by po or ip methaqualone pretreatment suggesting the possibility of noninducible forms of renal and neuronal esterases/amidases.

Selective stimulation of carboxylesterases metabolizing charged steroid esters by hydrocortisone

We observed a remarkable augmentation in the rate of hydrolytic breakdown of HCHS following exposure to corticosteroid therapy. This underscores the need for a careful reappraisal of its dosage in long term therapy. In such an event the uncharged ester may be the preferred drug of choice.

Effect of Anti-Inflammatory Thiosemicarbazone Indoles on Hyaluronidase, Acid Phosphatase and Trypsin

The present study was designed to evaluate the molecular basis of anti-inflammatory effects of nine 2-aryl-3-[4-(substituted phenyl)-3-thiosemicarbazone] indoles and their interaction with lysosomal and proteolytic enzymes. All compounds exhibited anti-inflammatory activity, which was reflected by 5-67% reduction in carrageenin-induced oedema in rat. Substituted thiosemicarbazone indoles caused concentration-dependent inhibition of hyaluronidase activity in vitro while the activities of acid phosphatase and trypsin were unaltered. Substitution of the aryl group attached to indole moiety resulted in a 2- to 3-fold increase in hyaluronidase inhibition by these compounds. Preincubation of the compounds with hyaluronidase produced time-dependent inactivation of the enzyme. Determination of enzyme inhibition kinetics with 2-aryl-3-[4-(2-methylphenyl)-3-thiosemicarbazone] indole by Lineweaver-Burk and Dixon plots indicated competitive nature of hyaluronidase-compound interaction. These studies failed to demonstrate any definite relationship between anti-inflammatory activity and hyaluronidase inhibition.