Effects of inducers and inhibitors of cytochrome P-450-linked monooxygenases on the toxicity, in vitro metabolism and in vivo irreversible binding of 2-methylnaphthalene in mice

Kathryn A Griffin; Collin B Johnson; Robert K Breger; R B Franklin

doi:10.1016/S0022-3565(25)33093-4

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Effects of inducers and inhibitors of cytochrome P-450-linked monooxygenases on the toxicity, in vitro metabolism and in vivo irreversible binding of 2-methylnaphthalene in mice

Journal article

Peer reviewed

Effects of inducers and inhibitors of cytochrome P-450-linked monooxygenases on the toxicity, in vitro metabolism and in vivo irreversible binding of 2-methylnaphthalene in mice

Kathryn A Griffin, Collin B Johnson, Robert K Breger and R B Franklin

The Journal of pharmacology and experimental therapeutics, Vol.221(3), pp.517-524

06/1982

DOI: 10.1016/S0022-3565(25)33093-4

PMID: 7086669

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Abstract

A dose of [14C]2-methylnaphthalene (2-MN; 400 mg/kg i.p.) accumulated in C57BL/6J mice in the fat > kidney > liver > lung. Maximal levels were reached 2 to 4 hr after administration and the half-life of elimination of radioactivity from the blood was approximately 3 hr. The cytochrome P-450-linked-monooxygenase-inducing agents phenobarbital (PB) and 3-methylcholanthrene (3-MC) decreased the pulmonary toxicity of 2-MN in C57BL/6J mice, but only PB significantly decreased the in vivo irreversible binding of 2-MN in the lung; 3-MC had no effect. Piperonyl butoxide significantly decreased the binding in the lung, liver and kidney, but had no effect on the pulmonary toxicity. SKF 525-A had no effect on the extent of pulmonary necrosis. In the liver, PB and 3-MC did not significantly decrease the binding. Diethylmaleate had no significant effects on hepatic binding, but did decrease the pulmonary and renal binding. Diethylmaleate had no effect on the severity of the pulmonary lesion, but enhanced the lethality of 2-MN. PB significantly increased the hepatic in vitro microsomal metabolism of 2-MN to dihydrodiols, but PB had no effect on the metabolism in the lung, whereas 3-MC significantly decreased dihydrodiol formation. Pretreatment of mice with piperonyl butoxide and diethylmaleate had no significant effects on microsomal hepatic or pulmonary in vitro dihydrodiol formation. 2-MN (400 mg/kg i.p.) also caused a significant depletion of hepatic glutathione 3 to 6 hr after administration, but had no effect on pulmonary or renal levels. The data suggest that metabolism may play a role in the pulmonary toxicity due to 2-MN, but the role of dihydrodiol formation or in vivo irreversible binding as an index of toxicity is as yet uncertain.

Animals

Cytochrome P-450 Enzyme System - metabolism

Enzyme Induction - drug effects

Male

Methylcholanthrene - pharmacology

Mice

Mice, Inbred C57BL

Mixed Function Oxygenases - antagonists & inhibitors

Mixed Function Oxygenases - metabolism

Naphthalenes - metabolism

Oxidoreductases - metabolism

Phenobarbital - pharmacology

Piperonyl Butoxide - pharmacology

Proadifen - pharmacology

Details

Title: Subtitle: Effects of inducers and inhibitors of cytochrome P-450-linked monooxygenases on the toxicity, in vitro metabolism and in vivo irreversible binding of 2-methylnaphthalene in mice
Creators: Kathryn A Griffin
Collin B Johnson
Robert K Breger
R B Franklin
Resource Type: Journal article
Publication Details: The Journal of pharmacology and experimental therapeutics, Vol.221(3), pp.517-524
DOI: 10.1016/S0022-3565(25)33093-4
PMID: 7086669
ISSN: 0022-3565
eISSN: 1521-0103
Grant note: HL 24262 / NHLBI NIH HHS
Language: English
Date published: 06/1982
Academic Unit: Cardiovascular Medicine; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984210514702771

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