Book of Abstmcts - EUROTOX 94 91

able to assay cytokines by ELISA in Cynomolgus monkeys, dogs or micro-pigs, the cross reactivities of a panel of commercially available human ELISA kits were studied in these animal species. Production of interfeukin 18 (IL-11). IL-2, 11-6, tumor necrosis factor* (TNFa). and interferon-y (IFN-y) was triggered by lipopofysaccharide and phy- tohemagglutinin in cultures of peripheral blood mononuclear cells from humans, Cynomolgus monkeys, dogs and micro-pigs.

No cross reactions were observed between humans, dogs and micro-pigs whatever the cytokine considered. By contrast, monkey 11-18, IL-2 and IL-6 but neither TNF-ar nor IFN-I, were detected using human reagents. In addition, the kinetics and production level of these cytokines compared well in humans and Cynomolgus monkeys.

These results suggest that human ELISA kits can be use to measure cytokine production in Cynomolgus monkeys to study the modulation of the himune system.

Key words: immunotoxicity; cytokine; monkey; ELISA

lnductlve Effect of Tobacco Smoke on Mouse Pulmonary and Hepatlc Cytochrome P450

Isoforms PH. Villard. E. Seree, B. Lacarelle. M.C. Therene-Fenoglio, L. Attolini, B. Bruguerole, Y. Barra, A. Durand, J. Catalin. EA 859, Laboratoire de Pharmacocinkique et EA 878, Laboratoire de G&ie g&tique et Biotechnologie. AwIt de Pharmacie. 13385 Marseille Cedex 5

Many studies have demonstrated the inductive effect of cigarette smoke on liver cytochromes P450 CYPlAl and CYPlA2. However, little is known concerning its effect on other isoforms. notably in lungs which are the target organs for smoke compounds.

Male NMRI mice were daily exposed to tobacco smoke, equivalent to 3 cigarettes (Gitanes), during 4 (S4) or 8 (Se) days, using a HAMBURG II smoking machine (norm IS0 3308).

In liver microsomes. the total cytochromes P450 concentration decreases by 18.4% and 28.5% for groups S4 and S8 respectively. The cytochrome b5 concentration increases by 17.7% and 6.17%. Hepatic enzymatic activities ethoxyresorufine 0-deethylase, aminopyrine Ndemethylase, riinaprine dhydroxylase, p-nitrophenol hydroxylase, and erythromycin Ndemethylase; representative of CYPl Al, CYP2C. CYP2D. CYFZEl , and CYP3A respectively were induced in both groups. However, the pentoxyresorufine Odealkylase activity, catalyzed byCYP2B. was only induced in group S8.

Western blots analysis, performed on liver microsomes, showed that CYPl Al increased 1.34 and 2.04fold. CYP3A increased 2.14 and 2.28 fold, in group S4 and S8 respectively. CYPSEl increased only in S8 group (1.25 fold). On pulmonary microsomes no CYP3A proteins were detected, CYPl Al increased 1.33 and 1.13 fold, CYP2El was markedly enhanced in both groups (2.15 and 6.76 fold).

We demonstrated that cigarette smoke induces a large variety of cytochrome P450 isoforms in liver and lungs. Moreover, smoking is one of the greatz .tsk factors in the induction of lung cancers. Authors proposed that lung cancer is well correlated with the pulmonary enhanced expression of CYPlA subfamily Our results suggest that CYP2El which is implicated in precarcinogens bioactivation. is in lung more inducible than CVPlAl and could have a predominant role in pulmonary carcinogenesis.

This work was supported by A.Pl?A. and Ligue Nationale Contre Le Cancer (Comite du Var).

Key wordo: cytochromes P450; induction; liver; lung; tobacco smoke

Cooperutlve Environmental Program for Toxic Pollutants In Central and Ea&rn Europe

Rvtis Virbalis. Laboratory of Biochemical Ecology of Kaunas MedicalAcademg &thuania

Lithuania as well as other Eastern and Central Europe countries is faced growing environmental pollution by heavy metals, This problem may be solved most effectively by inte! national cooperation program. Such program must include:

(1 )Total screening of all population who live in the contaminated by heavy metals environment by detailed complex investigations.

(2) The programs of experimental investigations to determine mechanisms of heavy metals small doses toxicity and combined action of heavy metals and other toxic substances.

(3) The mathematical models for such research. (4) The new methods of early diagnostics of such chronic intoxications including new biomarkers. (5) The searching of new antidots to heavy metals. (6) The specific prevention based on keeping of balance between trace elements and heavy metals. Appropriate elements of this program realised in Lithuania for the children who Iii in polluted regions gave some

effects. Pilot comparative epidemiological studies dealing with relations between appropriate pathology groups and exposure to toxic environmental contaminants are good start point of such cooperation.