Effect of coadministration of antituberculous drugs on the hepatic drug metabolizing enzymes and oxidative stress in the mouse

Kota Ramana, K. K. Kohli

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Objective: To investigate whether the coadministration of isoniazid (INH), rifampicin (RMP) and pyrazinamide (PZA) was more potent than RMP alone in the induction of drug metabolizing enzymes and the causation of oxidative stress in the mouse. Methods: Male mice were administered intraperitoneally 40 mg RMP or simultaneously 40, 40 and 80 mg INH, RMP and PZA per Kg body weight for 3 days. The livers were homogenized in potassium phosphate buffer containing potassium chloride. Microsomes and 100,000 x g supernatant were prepared by differential centrifugation. Assays of cytochrome P450, NADPH cytochrome c reductase, erythromycin N-demethylase and lipid peroxidation were performed in the microsomes. Assays of glutathione reductase, glutathione peroxidase and catalase were performed in 100,000 x g supernatant. Glutathione was assayed in supernatant from 5% TCA homogenate of the liver specimen. Results: Coadministration of INH, RMP and PZA increased the hepatic microsomal cytochrome P450, lipid peroxidation, the activities of NADPH cytochrome c oxidoreductase, erythromycin N-demethylase, Se-independent glutathione peroxidase and intensified 53.5 and 56 kDa polypeptides in the mouse. RMP increased all these parameters except the activity of selenium independent glutathione peroxidase. However, changes caused in the lipid peroxidation and the activity of erythromycin N-demethylase by coadministration of INH, RMP and PZA were more dramatic as compared to RMP. Both treatments did not alter the hepatic glutathione and activities of glutathione reductase, Se-dependent glutathione peroxidase, superoxide dismutase but decreased the activity of catalase in the mouse. Conclusion: Coadministration of INH, RMP and PZA was more potent in the induction of the hepatic microsomal erythromycin N-demethylase and causation of oxidative stress in the mouse as compared to RMP administration alone.

Original languageEnglish (US)
Pages (from-to)299-305
Number of pages7
JournalIndian Journal of Pharmacology
Volume31
Issue number4
StatePublished - Aug 1999
Externally publishedYes

Fingerprint

Rifampin
Oxidative Stress
Pyrazinamide
Liver
Enzymes
Cytochrome P-450 CYP3A
Pharmaceutical Preparations
Glutathione Peroxidase
Lipid Peroxidation
Glutathione Reductase
Microsomes
Causality
Catalase
Cytochrome P-450 Enzyme System
Glutathione
NADPH-Ferrihemoprotein Reductase
Potassium Chloride
Isoniazid
Cytochromes c
Centrifugation

Keywords

  • Drug metabolism
  • Isoniazid
  • Mouse
  • Oxidative stress
  • Pyrazinamide
  • Rifampicin

ASJC Scopus subject areas

  • Pharmacology

Cite this

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title = "Effect of coadministration of antituberculous drugs on the hepatic drug metabolizing enzymes and oxidative stress in the mouse",
abstract = "Objective: To investigate whether the coadministration of isoniazid (INH), rifampicin (RMP) and pyrazinamide (PZA) was more potent than RMP alone in the induction of drug metabolizing enzymes and the causation of oxidative stress in the mouse. Methods: Male mice were administered intraperitoneally 40 mg RMP or simultaneously 40, 40 and 80 mg INH, RMP and PZA per Kg body weight for 3 days. The livers were homogenized in potassium phosphate buffer containing potassium chloride. Microsomes and 100,000 x g supernatant were prepared by differential centrifugation. Assays of cytochrome P450, NADPH cytochrome c reductase, erythromycin N-demethylase and lipid peroxidation were performed in the microsomes. Assays of glutathione reductase, glutathione peroxidase and catalase were performed in 100,000 x g supernatant. Glutathione was assayed in supernatant from 5{\%} TCA homogenate of the liver specimen. Results: Coadministration of INH, RMP and PZA increased the hepatic microsomal cytochrome P450, lipid peroxidation, the activities of NADPH cytochrome c oxidoreductase, erythromycin N-demethylase, Se-independent glutathione peroxidase and intensified 53.5 and 56 kDa polypeptides in the mouse. RMP increased all these parameters except the activity of selenium independent glutathione peroxidase. However, changes caused in the lipid peroxidation and the activity of erythromycin N-demethylase by coadministration of INH, RMP and PZA were more dramatic as compared to RMP. Both treatments did not alter the hepatic glutathione and activities of glutathione reductase, Se-dependent glutathione peroxidase, superoxide dismutase but decreased the activity of catalase in the mouse. Conclusion: Coadministration of INH, RMP and PZA was more potent in the induction of the hepatic microsomal erythromycin N-demethylase and causation of oxidative stress in the mouse as compared to RMP administration alone.",
keywords = "Drug metabolism, Isoniazid, Mouse, Oxidative stress, Pyrazinamide, Rifampicin",
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TY - JOUR

T1 - Effect of coadministration of antituberculous drugs on the hepatic drug metabolizing enzymes and oxidative stress in the mouse

AU - Ramana, Kota

AU - Kohli, K. K.

PY - 1999/8

Y1 - 1999/8

N2 - Objective: To investigate whether the coadministration of isoniazid (INH), rifampicin (RMP) and pyrazinamide (PZA) was more potent than RMP alone in the induction of drug metabolizing enzymes and the causation of oxidative stress in the mouse. Methods: Male mice were administered intraperitoneally 40 mg RMP or simultaneously 40, 40 and 80 mg INH, RMP and PZA per Kg body weight for 3 days. The livers were homogenized in potassium phosphate buffer containing potassium chloride. Microsomes and 100,000 x g supernatant were prepared by differential centrifugation. Assays of cytochrome P450, NADPH cytochrome c reductase, erythromycin N-demethylase and lipid peroxidation were performed in the microsomes. Assays of glutathione reductase, glutathione peroxidase and catalase were performed in 100,000 x g supernatant. Glutathione was assayed in supernatant from 5% TCA homogenate of the liver specimen. Results: Coadministration of INH, RMP and PZA increased the hepatic microsomal cytochrome P450, lipid peroxidation, the activities of NADPH cytochrome c oxidoreductase, erythromycin N-demethylase, Se-independent glutathione peroxidase and intensified 53.5 and 56 kDa polypeptides in the mouse. RMP increased all these parameters except the activity of selenium independent glutathione peroxidase. However, changes caused in the lipid peroxidation and the activity of erythromycin N-demethylase by coadministration of INH, RMP and PZA were more dramatic as compared to RMP. Both treatments did not alter the hepatic glutathione and activities of glutathione reductase, Se-dependent glutathione peroxidase, superoxide dismutase but decreased the activity of catalase in the mouse. Conclusion: Coadministration of INH, RMP and PZA was more potent in the induction of the hepatic microsomal erythromycin N-demethylase and causation of oxidative stress in the mouse as compared to RMP administration alone.

AB - Objective: To investigate whether the coadministration of isoniazid (INH), rifampicin (RMP) and pyrazinamide (PZA) was more potent than RMP alone in the induction of drug metabolizing enzymes and the causation of oxidative stress in the mouse. Methods: Male mice were administered intraperitoneally 40 mg RMP or simultaneously 40, 40 and 80 mg INH, RMP and PZA per Kg body weight for 3 days. The livers were homogenized in potassium phosphate buffer containing potassium chloride. Microsomes and 100,000 x g supernatant were prepared by differential centrifugation. Assays of cytochrome P450, NADPH cytochrome c reductase, erythromycin N-demethylase and lipid peroxidation were performed in the microsomes. Assays of glutathione reductase, glutathione peroxidase and catalase were performed in 100,000 x g supernatant. Glutathione was assayed in supernatant from 5% TCA homogenate of the liver specimen. Results: Coadministration of INH, RMP and PZA increased the hepatic microsomal cytochrome P450, lipid peroxidation, the activities of NADPH cytochrome c oxidoreductase, erythromycin N-demethylase, Se-independent glutathione peroxidase and intensified 53.5 and 56 kDa polypeptides in the mouse. RMP increased all these parameters except the activity of selenium independent glutathione peroxidase. However, changes caused in the lipid peroxidation and the activity of erythromycin N-demethylase by coadministration of INH, RMP and PZA were more dramatic as compared to RMP. Both treatments did not alter the hepatic glutathione and activities of glutathione reductase, Se-dependent glutathione peroxidase, superoxide dismutase but decreased the activity of catalase in the mouse. Conclusion: Coadministration of INH, RMP and PZA was more potent in the induction of the hepatic microsomal erythromycin N-demethylase and causation of oxidative stress in the mouse as compared to RMP administration alone.

KW - Drug metabolism

KW - Isoniazid

KW - Mouse

KW - Oxidative stress

KW - Pyrazinamide

KW - Rifampicin

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M3 - Article

VL - 31

SP - 299

EP - 305

JO - Indian Journal of Pharmacology

JF - Indian Journal of Pharmacology

SN - 0253-7613

IS - 4

ER -