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Oulun yliopiston väitöskirjat

METABOLISM AND INTERACTIONS OF PESTICIDES IN HUMAN AND ANIMAL IN VITRO HEPATIC MODELS, ACTA UNIVERSITATIS OULUENSIS D Medica 1071

ISBN-13:	978-951-42-6298-2
Kieli:	englanti
Kustantaja:	Oulun yliopisto
Oppiaine:	Lääketiede, farmasia
Painosvuosi:	2010
Sidosasu:	pehmeäkantinen
Sijainti:	Print Tietotalo
Sivumäärä:	174
Tekijät:	ABASS KHALED M.

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Risk assessment of chemicals needs reliable scientific information and one source of informationis the characterization of the metabolic fate and toxicokinetics of a chemical. Metabolism is oftenthe most important factor contributing to toxicokinetics. Cytochrome P450 (CYP) enzymes are asuperfamily of microsomal proteins playing a pivotal role in xenobiotic metabolism. In the present study, pesticides were used as representative xenobiotics since exposure topesticides is a global challenge to risk assessment. Human and animal in vitro hepatic models wereapplied with the advantage of novel analytical techniques (LC/TOF-MS and LC/MS-MS) toelucidate the in vitro metabolism and interaction of selected pesticides. The results of these studies demonstrate that CYP enzymes catalyze the bioactivation ofprofenofos, diuron and carbosulfan into their more toxic metabolites desthiopropylprofenofos, N-demethyldiuron and carbofuran, respectively. The suspected carcinogenic metabolite ofmetalaxyl, 2,6-dimethylaniline, was not detected. CYP3A4 and CYP2C19 activities may beimportant in determining the toxicity arising from exposure to profenofos and carbosulfan.Individuals with high CYP1A2 and CYP2C19 activities might be more susceptible to diurontoxicity. Qualitative results of in vitro metabolism were generally in agreement with the results obtainedfrom the published in vivo data, at least for the active chemical moiety and major metabolites.Considerable differences in the quantities of the metabolites produced within the species, as wellas in the ratios of the metabolites among the species, were observed. These findings illustrate that in vitro screening of qualitative and quantitative differences areneeded to provide a firm basis for interspecies and in vitro-in vivo extrapolations. Based on ourfindings, in vitro-in vivo extrapolation based on the elucidation of the in vitro metabolic pattern ofpesticides in human and animal hepatic models could be a good model for understanding andextending the results of pesticides metabolism studies to human health risk assessment.

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