Effects of cimetidine on theophylline, acetaminophen, and zoxazolamine toxicity in the intact mouse

R. A. Lazarte, S. W. bigelow, D. W. Nebert, Roy C Levitt

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

3-Methylcholanthrene treatment of C57BL/6N mice induces significant amounts of cytochrome P1-450, whereas P1-450 levels in 3-methylcholanthrene-treated DBA/2N mice are no different from those in control C57BL/6N or DBA/2N mice. Comparison of 3-methylcholanthrene-treated C57BL/6N and DBA/2N mice thus provides a convenient means of determining the role of P1-450 metabolism in two strains of mice following identical drug treatment regimens. 3-Methylcholanthrene-induced P1-450 is shown to be more effective than other forms of P-450 in detoxifying theophylline and zoxazolamine and in enhancing the toxicity of acetaminophen. Cimetidine in vivo blocks these metabolic pathways, resulting in increased toxicity of theophylline and zoxazolamine and protection against acetaminophen toxicity. These data illustrate the double-edged sword nature of P1-450 metabolism and the possibility of a paradoxical effect of cimetidine during drug-drug interactions in vivo. Cimetidine is shown to inhibit in vivo and in vitro the metabolism by both 3-methylcholanthrene-induced P1-450 and control forms of P-450; these data suggest that cimetidine may be acting at the level of P-450 reduction by NADPH-P-450 oxidoreductase. This same mechanism of action has been previously suggested for ellipticine.

Original languageEnglish
Pages (from-to)21-29
Number of pages9
JournalDevelopmental Pharmacology and Therapeutics
Volume7
Issue number1
StatePublished - Feb 23 1984
Externally publishedYes

Fingerprint

Zoxazolamine
Methylcholanthrene
Cimetidine
Theophylline
Acetaminophen
Inbred DBA Mouse
ellipticine
Cytochromes
Metabolic Networks and Pathways
NADP
Drug Interactions
Inbred C57BL Mouse
Pharmaceutical Preparations
Oxidoreductases

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Effects of cimetidine on theophylline, acetaminophen, and zoxazolamine toxicity in the intact mouse. / Lazarte, R. A.; bigelow, S. W.; Nebert, D. W.; Levitt, Roy C.

In: Developmental Pharmacology and Therapeutics, Vol. 7, No. 1, 23.02.1984, p. 21-29.

Research output: Contribution to journalArticle

@article{0be514845a31456b89278d78e4efb724,
title = "Effects of cimetidine on theophylline, acetaminophen, and zoxazolamine toxicity in the intact mouse",
abstract = "3-Methylcholanthrene treatment of C57BL/6N mice induces significant amounts of cytochrome P1-450, whereas P1-450 levels in 3-methylcholanthrene-treated DBA/2N mice are no different from those in control C57BL/6N or DBA/2N mice. Comparison of 3-methylcholanthrene-treated C57BL/6N and DBA/2N mice thus provides a convenient means of determining the role of P1-450 metabolism in two strains of mice following identical drug treatment regimens. 3-Methylcholanthrene-induced P1-450 is shown to be more effective than other forms of P-450 in detoxifying theophylline and zoxazolamine and in enhancing the toxicity of acetaminophen. Cimetidine in vivo blocks these metabolic pathways, resulting in increased toxicity of theophylline and zoxazolamine and protection against acetaminophen toxicity. These data illustrate the double-edged sword nature of P1-450 metabolism and the possibility of a paradoxical effect of cimetidine during drug-drug interactions in vivo. Cimetidine is shown to inhibit in vivo and in vitro the metabolism by both 3-methylcholanthrene-induced P1-450 and control forms of P-450; these data suggest that cimetidine may be acting at the level of P-450 reduction by NADPH-P-450 oxidoreductase. This same mechanism of action has been previously suggested for ellipticine.",
author = "Lazarte, {R. A.} and bigelow, {S. W.} and Nebert, {D. W.} and Levitt, {Roy C}",
year = "1984",
month = "2",
day = "23",
language = "English",
volume = "7",
pages = "21--29",
journal = "Developmental Pharmacology and Therapeutics",
issn = "0379-8305",
publisher = "S. Karger AG",
number = "1",

}

TY - JOUR

T1 - Effects of cimetidine on theophylline, acetaminophen, and zoxazolamine toxicity in the intact mouse

AU - Lazarte, R. A.

AU - bigelow, S. W.

AU - Nebert, D. W.

AU - Levitt, Roy C

PY - 1984/2/23

Y1 - 1984/2/23

N2 - 3-Methylcholanthrene treatment of C57BL/6N mice induces significant amounts of cytochrome P1-450, whereas P1-450 levels in 3-methylcholanthrene-treated DBA/2N mice are no different from those in control C57BL/6N or DBA/2N mice. Comparison of 3-methylcholanthrene-treated C57BL/6N and DBA/2N mice thus provides a convenient means of determining the role of P1-450 metabolism in two strains of mice following identical drug treatment regimens. 3-Methylcholanthrene-induced P1-450 is shown to be more effective than other forms of P-450 in detoxifying theophylline and zoxazolamine and in enhancing the toxicity of acetaminophen. Cimetidine in vivo blocks these metabolic pathways, resulting in increased toxicity of theophylline and zoxazolamine and protection against acetaminophen toxicity. These data illustrate the double-edged sword nature of P1-450 metabolism and the possibility of a paradoxical effect of cimetidine during drug-drug interactions in vivo. Cimetidine is shown to inhibit in vivo and in vitro the metabolism by both 3-methylcholanthrene-induced P1-450 and control forms of P-450; these data suggest that cimetidine may be acting at the level of P-450 reduction by NADPH-P-450 oxidoreductase. This same mechanism of action has been previously suggested for ellipticine.

AB - 3-Methylcholanthrene treatment of C57BL/6N mice induces significant amounts of cytochrome P1-450, whereas P1-450 levels in 3-methylcholanthrene-treated DBA/2N mice are no different from those in control C57BL/6N or DBA/2N mice. Comparison of 3-methylcholanthrene-treated C57BL/6N and DBA/2N mice thus provides a convenient means of determining the role of P1-450 metabolism in two strains of mice following identical drug treatment regimens. 3-Methylcholanthrene-induced P1-450 is shown to be more effective than other forms of P-450 in detoxifying theophylline and zoxazolamine and in enhancing the toxicity of acetaminophen. Cimetidine in vivo blocks these metabolic pathways, resulting in increased toxicity of theophylline and zoxazolamine and protection against acetaminophen toxicity. These data illustrate the double-edged sword nature of P1-450 metabolism and the possibility of a paradoxical effect of cimetidine during drug-drug interactions in vivo. Cimetidine is shown to inhibit in vivo and in vitro the metabolism by both 3-methylcholanthrene-induced P1-450 and control forms of P-450; these data suggest that cimetidine may be acting at the level of P-450 reduction by NADPH-P-450 oxidoreductase. This same mechanism of action has been previously suggested for ellipticine.

UR - http://www.scopus.com/inward/record.url?scp=0021351698&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0021351698&partnerID=8YFLogxK

M3 - Article

C2 - 6697867

AN - SCOPUS:0021351698

VL - 7

SP - 21

EP - 29

JO - Developmental Pharmacology and Therapeutics

JF - Developmental Pharmacology and Therapeutics

SN - 0379-8305

IS - 1

ER -