Isometamidium metabolism and distribution in rat hepatocytes

I. Boibessot, M.H. Grant, G.G. Skellern, D.G. Watson

Research output: Contribution to conferencePaper

Abstract

Little is known about the metabolism and mechanism of action of the trypanocide, isometamidium (ISM), the major drug used for prophylaxis of trypanosomiasis. We have investigated its metabolism and distribution in isolated rat hepatocytes using liquid chromatography-mass spectrometry and confocal laser scanning microscopy (CLSM). Two putative metabolites were formed, which were proposed to be a mono-acetyl derivative and an oxidized metabolite (SII). This is the first demonstration of the hepatic metabolism of ISM, as previous in vivo studies were hampered by dose-limiting toxicity and insensitive analytical methods. The intrinsic fluorescence of the drug enabled its intracellular uptake to be followed by CLSM. It is taken up rapidly into the nucleolus, nuclear membrane and endoplasmic reticulum within 5 min, and retained in the nucleus for at least 24 h. Persistent binding of ISM to cellular macromolecules may contribute to its prophylactic effect in vivo. Pretreatment of rats with 3-methylcholanthrene, phenobarbitone (PB) or the widely used pyrethroid pesticide, deltamethrin, resulted in an increase in metabolism of ISM to the proposed SII after 1 h incubation with hepatocytes. 3-methylcholanthrene was the most potent inducer, causing a maximal 19.5-fold induction of SII formation after exposure of hepatocytes to ISM for 1 h compared with formation by control hepatocytes. In comparison, at the 1 h timepoint deltamethrin pre-treatment caused a 10.2-fold induction, and PB only 8.2 fold.

Conference

Conference26th Meeting of the International Scientific Council for Trypanosomiasis Research and Control
CountryBurkina Faso
CityOuagadougou
Period1/10/015/10/01

Fingerprint

Hepatocytes
Methylcholanthrene
Phenobarbital
Confocal Microscopy
Trypanocidal Agents
Pyrethrins
Trypanosomiasis
Nuclear Envelope
Pesticides
Liquid Chromatography
Endoplasmic Reticulum
Pharmaceutical Preparations
Mass Spectrometry
Fluorescence
isometamidium chloride
Liver
decamethrin

Keywords

  • isometamidium metabolism
  • rat hepatocytes
  • bioengineering
  • trypanocide

Cite this

Boibessot, I., Grant, M. H., Skellern, G. G., & Watson, D. G. (2001). Isometamidium metabolism and distribution in rat hepatocytes. Paper presented at 26th Meeting of the International Scientific Council for Trypanosomiasis Research and Control, Ouagadougou, Burkina Faso.
Boibessot, I. ; Grant, M.H. ; Skellern, G.G. ; Watson, D.G. / Isometamidium metabolism and distribution in rat hepatocytes. Paper presented at 26th Meeting of the International Scientific Council for Trypanosomiasis Research and Control, Ouagadougou, Burkina Faso.
@conference{9e96c3e29ad5424c84641581e402c9fd,
title = "Isometamidium metabolism and distribution in rat hepatocytes",
abstract = "Little is known about the metabolism and mechanism of action of the trypanocide, isometamidium (ISM), the major drug used for prophylaxis of trypanosomiasis. We have investigated its metabolism and distribution in isolated rat hepatocytes using liquid chromatography-mass spectrometry and confocal laser scanning microscopy (CLSM). Two putative metabolites were formed, which were proposed to be a mono-acetyl derivative and an oxidized metabolite (SII). This is the first demonstration of the hepatic metabolism of ISM, as previous in vivo studies were hampered by dose-limiting toxicity and insensitive analytical methods. The intrinsic fluorescence of the drug enabled its intracellular uptake to be followed by CLSM. It is taken up rapidly into the nucleolus, nuclear membrane and endoplasmic reticulum within 5 min, and retained in the nucleus for at least 24 h. Persistent binding of ISM to cellular macromolecules may contribute to its prophylactic effect in vivo. Pretreatment of rats with 3-methylcholanthrene, phenobarbitone (PB) or the widely used pyrethroid pesticide, deltamethrin, resulted in an increase in metabolism of ISM to the proposed SII after 1 h incubation with hepatocytes. 3-methylcholanthrene was the most potent inducer, causing a maximal 19.5-fold induction of SII formation after exposure of hepatocytes to ISM for 1 h compared with formation by control hepatocytes. In comparison, at the 1 h timepoint deltamethrin pre-treatment caused a 10.2-fold induction, and PB only 8.2 fold.",
keywords = "isometamidium metabolism, rat hepatocytes, bioengineering, trypanocide",
author = "I. Boibessot and M.H. Grant and G.G. Skellern and D.G. Watson",
note = "I. Boibessot, I., Tettey, J.N.A., Skellern, G.G., WATSON, D.G., Grant, M.H. Metabolism of isometamidium in hepatocytes isolated from control and inducer-treated rats. Journal of Veterinary Pharmacology and Therapeutics Volume 29 Issue 6, Pages 547 - 553; 26th Meeting of the International Scientific Council for Trypanosomiasis Research and Control ; Conference date: 01-10-2001 Through 05-10-2001",
year = "2001",
language = "English",

}

Boibessot, I, Grant, MH, Skellern, GG & Watson, DG 2001, 'Isometamidium metabolism and distribution in rat hepatocytes' Paper presented at 26th Meeting of the International Scientific Council for Trypanosomiasis Research and Control, Ouagadougou, Burkina Faso, 1/10/01 - 5/10/01, .

Isometamidium metabolism and distribution in rat hepatocytes. / Boibessot, I.; Grant, M.H.; Skellern, G.G.; Watson, D.G.

2001. Paper presented at 26th Meeting of the International Scientific Council for Trypanosomiasis Research and Control, Ouagadougou, Burkina Faso.

Research output: Contribution to conferencePaper

TY - CONF

T1 - Isometamidium metabolism and distribution in rat hepatocytes

AU - Boibessot, I.

AU - Grant, M.H.

AU - Skellern, G.G.

AU - Watson, D.G.

N1 - I. Boibessot, I., Tettey, J.N.A., Skellern, G.G., WATSON, D.G., Grant, M.H. Metabolism of isometamidium in hepatocytes isolated from control and inducer-treated rats. Journal of Veterinary Pharmacology and Therapeutics Volume 29 Issue 6, Pages 547 - 553

PY - 2001

Y1 - 2001

N2 - Little is known about the metabolism and mechanism of action of the trypanocide, isometamidium (ISM), the major drug used for prophylaxis of trypanosomiasis. We have investigated its metabolism and distribution in isolated rat hepatocytes using liquid chromatography-mass spectrometry and confocal laser scanning microscopy (CLSM). Two putative metabolites were formed, which were proposed to be a mono-acetyl derivative and an oxidized metabolite (SII). This is the first demonstration of the hepatic metabolism of ISM, as previous in vivo studies were hampered by dose-limiting toxicity and insensitive analytical methods. The intrinsic fluorescence of the drug enabled its intracellular uptake to be followed by CLSM. It is taken up rapidly into the nucleolus, nuclear membrane and endoplasmic reticulum within 5 min, and retained in the nucleus for at least 24 h. Persistent binding of ISM to cellular macromolecules may contribute to its prophylactic effect in vivo. Pretreatment of rats with 3-methylcholanthrene, phenobarbitone (PB) or the widely used pyrethroid pesticide, deltamethrin, resulted in an increase in metabolism of ISM to the proposed SII after 1 h incubation with hepatocytes. 3-methylcholanthrene was the most potent inducer, causing a maximal 19.5-fold induction of SII formation after exposure of hepatocytes to ISM for 1 h compared with formation by control hepatocytes. In comparison, at the 1 h timepoint deltamethrin pre-treatment caused a 10.2-fold induction, and PB only 8.2 fold.

AB - Little is known about the metabolism and mechanism of action of the trypanocide, isometamidium (ISM), the major drug used for prophylaxis of trypanosomiasis. We have investigated its metabolism and distribution in isolated rat hepatocytes using liquid chromatography-mass spectrometry and confocal laser scanning microscopy (CLSM). Two putative metabolites were formed, which were proposed to be a mono-acetyl derivative and an oxidized metabolite (SII). This is the first demonstration of the hepatic metabolism of ISM, as previous in vivo studies were hampered by dose-limiting toxicity and insensitive analytical methods. The intrinsic fluorescence of the drug enabled its intracellular uptake to be followed by CLSM. It is taken up rapidly into the nucleolus, nuclear membrane and endoplasmic reticulum within 5 min, and retained in the nucleus for at least 24 h. Persistent binding of ISM to cellular macromolecules may contribute to its prophylactic effect in vivo. Pretreatment of rats with 3-methylcholanthrene, phenobarbitone (PB) or the widely used pyrethroid pesticide, deltamethrin, resulted in an increase in metabolism of ISM to the proposed SII after 1 h incubation with hepatocytes. 3-methylcholanthrene was the most potent inducer, causing a maximal 19.5-fold induction of SII formation after exposure of hepatocytes to ISM for 1 h compared with formation by control hepatocytes. In comparison, at the 1 h timepoint deltamethrin pre-treatment caused a 10.2-fold induction, and PB only 8.2 fold.

KW - isometamidium metabolism

KW - rat hepatocytes

KW - bioengineering

KW - trypanocide

UR - http://dx.doi.org/10.1111/j.1365-2885.2006.00802.x

UR - http://www.au-ibar.org/isctrcmeetingAll.html

M3 - Paper

ER -

Boibessot I, Grant MH, Skellern GG, Watson DG. Isometamidium metabolism and distribution in rat hepatocytes. 2001. Paper presented at 26th Meeting of the International Scientific Council for Trypanosomiasis Research and Control, Ouagadougou, Burkina Faso.