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Pii: s0378-4274(03)90567-4

Poster Session P28. Biotransformation THE INHIBITION OF MALATHION DETOXICATION BY
ble incorporation of 54Fe in B(a)P/54Fe2O3 iron oxide mixtures in the ISOMALATHION AND OTHER OPTs IN HUMAN LIVER
hem moiety of CYP1A1. Statistically significant increases in cyp1a1 MICROSOMES
mRNA expressions and protein concentrations were observed in ratsexposed to B(a)P, to B(a)P-coated onto 56Fe F.M. Buratti, E. Testai. Laboratory of Comparative Toxicology and Ecotoxicology, Biochemical Toxicology Unity, Istituto Superiore di 2O3 particles, versus controls (p<0.01). Significant increases in EROD activities were seen in rats treated with B(a)P (p<0.001) or particularly with B(a)P-coated onto 56Fe2O3 particles An epidemic of malathion (MAL) poisonings occurring in Pakistan or with B(a)P-coated onto 54Fe2O3 particles, versus controls. In in 1976, affected 40% of spraymen and mixer working for a malaria addition, exposure to B(a)P/56Fe2O3 or 54Fe2O3 mixtures induced control programme. The episode evidenced the importance of impu- higher CYP1A1 protein concentrations and EROD activities, than rities, such as isomalathion (ISO), in the commercial formulations.
B(a)P alone (p<0.01). TOF-LMMS showed that the 54Fe/56Fe ratio Indeed, at the same level of exposure, about 2800 workers experi- in the microsomes of B(a)P-coated onto 54Fe2O3-instilled animals enced various degree of toxic effects related to the different contents was 1.3 instead of the theoretical 54Fe/56Fe ratio of 0.063. Animal of ISO in the commercial MAL formulations. ISO is formed during short-term exposure to B(a)P/Fe2O3 mixtures favored dramatically MAL manufacturing (usual content in commercial products 0.02%- the up-regulation of PAH-bioactivating CYP 1A1 enzymes in lungs, 0.2%); however these levels can significantly increase during storage, notably by interfering in its translation into functional hemoproteins.
especially at warm temperature. ISO potentiates MAL toxicity by Overall, this should lead to a better understanding of the underlying inhibiting carboxylesterase (CE), responsible for MAL detoxication.
mechanism involved in the enhanced carcinogenicity of B(a)P-coated As a consequence, a higher amount of MAL is desulfurated by hepatic CYPs to the toxic metabolite malaoxon. Furthermore, op-erators frequently use mixed formulation or different OPTs at thesame time, being concurrently exposed to different agents. We have TAXANES: ANTITUMOR EFFECTS AND INTERSPECIES
therefore characterized the human hepatic activity of CE toward DIFFERENCES IN METABOLISM
MAL in a panel of 20 human liver microsomes and the inhibitory R. Václavíková 1 , S. Horský 1, L. Svobodová 1 , B. Otová 2 , effect of ISO, chlorpyrifos (CPF) and parathion (PAR). CE activity P. Šimek 3, I. Gut 1. 1National Institute of Public Health, Prague, showed a low level of variation among individuals (4-fold). The CZ, 2First Medical Faculty, Charles University, Prague, CZ, reaction consists of two different phases with relatively low Km 3Institute of Entomology, CAS, Èeské Budìjovice, CZ values (Kmappa1=0.25–0.68µM; Kmapp2=1.7–12.4µM), confirmingfor CE a good MAL detoxifying activity. ISO resulted as a potent Taxanes are important recently introduced antineoplastic drugs. We non competitive inhibitor of MAL detoxication (Ki 0.62µM), with have investigated cytochrome P450 - catalyzed metabolism of pa- a higher efficiency than CPF and PAR (Ki =8.2µM and 50.2µM, clitaxel and docetaxel in rat, minipig, regular pig and human liver respectively). However, CPF-oxon, the toxic product of CPF desulfu- microsomes. In rat microsomes paclitaxel was metabolized mainly ration, showed the highest inhibitory potency towards CE-mediated to C3’-hydroxypaclitaxel (C3’-OHP), less to C2-hydroxypaclitaxel detoxication, being characterized by a Ki=22 nM. The present results (C2-OHP), di-hydroxypaclitaxel (di-OHP) and an unknown hydrox- evidence the importance of considering in risk assessment metabolic ypaclitaxel. In minipig microsomes, this unknown hydroxypaclitaxel interactions between chemicals to which humans can be concurrently was the main metabolite, whereas C3’-OHP and C2-OHP were minor products and the same held true for regular pig microsomes.
This work has been partially supported by the ISS Projects n° In human liver microsomes 6α-hydroxypaclitaxel (6α-OHP) was the main metabolite, followed by C3’-OHP, C2-OHP and two othermetabolites not yet fully characterized. However, the proportionof 6α-OHP and C3’-OHP in different human microsomes varied UP-REGULATION OF POLYCYCLIC AROMATIC
significantly. It became obvious that despite various general simi- HYDROCARBON-METABOLIZING CYTOCHROME
larities between human and pig metabolism reported, the profiles P4501A1 HEMOPROTEINS BY 56Fe2O3 OR 54Fe2O3
of paclitaxel metabolites in the studied species were different and FOLLOWING THE EXPOSURE OF SPRAGUE DAWLEY
6α-OHP remained a uniquely human metabolite. Among different RATS TO BENZO(A)PYRENE-COATED ONTO 56Fe2O3 OR
cDNA-expressed CYP enzymes (CYP1A2, 1B1, 2A6, 2C9, 2E1 and 54 Fe2O3 PARTICLES
3A4), only CYP3A4 enzyme formed C3’-OHP, C2-OHP and oneunknown metabolite.
P. Shirali 1 , B. Maunit 2 , F. Zerimech 3 , P. Gosset 4, C. Creusy 4, In regular pig, minipig and human liver microsomes, docetaxel J.F. Müller 3 , G. Garçon 1. 1Laboratoire de Recherche en (DXT) was metabolized mainly to hydroxydocetaxel (OHDTX), Toxicologie Industrielle et Environnementale, Université du Littoral whereas rat microsomes produced primarily diastereomeric hydrox- - Côte d’Opale, Dunkerque, France; 2Laboratoire de Spectrométrie yoxazolidinones. Human liver microsomes from different individuals de Masse et de Chimie Laser, Université de Metz, France; 3 formed OHDTX at different rates in relation to CYP3A4 content.
Laboratoire de Biochimie et de Biologie Moléculaire, Hôpital Significant blood levels of paclitaxel and docetaxel, respectively, Huriez, Lille, France; 4Laboratoire d’Anatomie et de Cytologie were reached after i.p.administration of the drugs to rats and Pathologique du Groupement Hospitalier de l’Institut Catholique de maintained for at least 6 hours. Upon repeated administration, these Lille, Faculté Libre de Médecine, Lille, France levels tended to decrease in case of paclitaxel; it possibly participated Any influence of iron in polycyclic aromatic hydrocarbon (PAH)/iron in a lower antitumor action of paclitaxel against s.c. lymphoma.
oxide mixtures on the capacity of PAHs to induce metabolizing en- Significant levels of C3’-OHP after paclitaxel and OHDTX after zymes will be one of many ways that iron oxides can affect docetaxel were detected in blood of the rats.
PAH carcinogenicity. A major point will be made regarding CYP: Acknowledgements: This study was supported by Grant IGA
they are hemoproteins. Hence, it will be of great interest to in- vestigate the possible involvement of Fe2O3 in benzo(a)pyrene(B(a)P)/Fe2O3 mixtures on the induction of PAH-metabolizing cy-tochrome P4501A1 (CYP1A1) enzymes on one of the first-entry EFFECT OF POLYVITAMIN COMPOSITION ON SOME
organ target, the lung. Male Sprague Dawley rats were intratra- HEPATIC P-450-DEPENDENT ENZYMES IN ISONIAZID
cheally instilled with hematite (56Fe2O3 or 54Fe2O3; 3 mg), B(a)P (3 AND RIFAMPICIN EXPOSURE RATS
mg) or B(a)P (3 mg)-coated onto hematite (56Fe2O3 or 54Fe2O3) par- V. Kovalenko 1,2 , A. Voronina 1 , A. Shayakhmetova 1,2 , ticles (3 mg). Firstly, lung mRNA expressions of cyp1a1 were carried O. Voloshina 2 , L. Berejna 1 . 1Institute of Pharmacology and out. Secondly, in view of the crucial role of CYP1A1 in the metabolic Toxicology, 2State Pharmacological Centre, Kyiv, Ukraine activation of B(a)P and its biochemical nature, protein concentrationsand catalytic activities (7-ethoxyresorufin O-deethylase; EROD) of Isoniazid and rifampicin are still widely used for the treatment of CYP1A1 were determined. Thirdly, time-of-flight laser microprobe tuberculosis. They may both cause liver damage after therapeutic mass spectrometry (TOF-LMMS) allowed us to determine the possi- doses are given. In this study we investigated the influence of these

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