Increased hepatotoxicity and cardiac fibrosis in cocaine-treated butyrylcholinesterase knockout mice

Ellen G. Duysen, Bin Li, Michaela Carlson, Yi Fan Li, Stacy Wieseler, Steven Heye Hinrichs, Oksana Lockridge

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23 Citations (Scopus)

Abstract

In mice, cocaine is detoxified to inactive products by butyrylcholinesterase (BChE) and carboxylesterase. In human beings, cocaine detoxification is primarily by BChE. The focus of this investigation was to elucidate the importance of BChE in reducing pathophysiological effects following cocaine exposure. Previous studies examining the effects of cocaine on BChE deficient animals relied on chemical inhibition of BChE with tetraisopropyl pyrophosphoramide (iso-OMPA). The creation of the BChE knockout mouse has provided a model for studying pathological effects of cocaine in mice free of chemical confounders. We hypothesized that mice with low or no BChE activity would have reduced cocaine metabolism, leading to hepatotoxicity and cardiomyopathy. A high-resolution in vivo imaging system recorded cardiac and respiratory function following treatment with a carboxylesterase inhibitor and a high dose of cocaine (100 mg/kg, intraperitoneally). The BChE-/- mice demonstrated depressed respiration through 12 hr after dosing and abnormal respiratory patterns consisting of a pause at full inspiration (apneusis), whereas BChE+/+ mice had recovered normal respiration rates by 30 min. after dosing and exhibited no apneusis. Liver and cardiac histology sections were analysed following a 20 mg/kg intraperitoneally dose of cocaine administered daily for 7 days. BChE-/- mice treated for 7 days with the chronic low dose showed significant hepatotoxicity and cardiac perivascular fibrosis compared to BChE+/+ mice. The observed functional changes following acute high-dose and chronic low-dose cocaine in BChE-/- and +/- mice warrants further investigation into the possibility of increased cocaine toxicity in human beings with BChE deficiency.

Original languageEnglish (US)
Pages (from-to)514-521
Number of pages8
JournalBasic and Clinical Pharmacology and Toxicology
Volume103
Issue number6
DOIs
StatePublished - Dec 1 2008

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Butyrylcholinesterase
Cocaine
Knockout Mice
Fibrosis
Carboxylesterase
Tetraisopropylpyrophosphamide
Detoxification
Histology
Respiratory Rate
Cardiomyopathies
Metabolism
Liver
Imaging systems
Respiration
Toxicity

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Cite this

Increased hepatotoxicity and cardiac fibrosis in cocaine-treated butyrylcholinesterase knockout mice. / Duysen, Ellen G.; Li, Bin; Carlson, Michaela; Li, Yi Fan; Wieseler, Stacy; Hinrichs, Steven Heye; Lockridge, Oksana.

In: Basic and Clinical Pharmacology and Toxicology, Vol. 103, No. 6, 01.12.2008, p. 514-521.

Research output: Contribution to journalArticle

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