Toxicology of Industrial Compounds

16
New Strategies: the Use of Long-term Cultures of
Hepatocytes in Toxicity Testing and Metabolism
Studies of Chemical Products Other than
Pharmaceuticals
VERA ROGIERS, 1 MAY AKRAWI, 2 SANDRA COECKE, 1
YVES VANDENBERGHE, 1 ELIZABETH SHEPHARD, 2 IAN
PHILLIPS 3 and ANTOINE VERCRUYSSE 1
1 Vrije Universiteit Brussel, Brussels; 2 University College
London, London; 3 University of London, London
Introduction: metabolism and toxicity of chemical
products are closely linked
Lipophilic compounds are metabolized in the liver by phase 1 and phase 2
reactions into more polar, more hydrophilic metabolites, which are usually
less biologically active. Bioactivation, however, may occur, forming toxic
species by phase 1, cytochrome P450 (CYP) dependent oxidation (e.g.
epoxidation of C=C to reactive epoxide intermediates (Guengerich et al.
1991), CYP dependent reduction (e.g. dehalogenation of CCl 4 toa free
radical intermediate) (Timbrell, 1993) or even by phase 2 reactions (e.g.
reactive episulphonium ion formation by glutathione conjugation of
dibromoethane) (Van Bladeren, 1988; Coles and Ketterer, 1990; Timbrell,
1993).
The major process involved in the bioactivation of chemical carcinogens
is their oxidation catalyzed by CYP enzymes. Thirty or more different CYP
forms exist within each animal species (Nebert et al., 1989), each with at
least some distinct elements of catalytic specificity and regulation. The role
of some of these CYPs in the activation and detoxication of chemical
carcinogens has already been determined. For example:
– CYP2E1 is a major catalyst involved in the oxidation of benzene,
styrene, CCl 4, CHCl 3, ethylene dichloride, vinylchloride, acrylonitrile,
vinyl carbamate (Guengerich et al., 1991), ethanol (Perrot et al., 1989),
dialkylnitrosamines (Yoo et al., 1988), isobutene (Cornet et al., 1991)
and some other small molecules.
– CYP1A1 is involved in the oxidation of polycyclic aromatic
hydrocarbons (Shimada et al., 1989b).
– CYP1A2 activates arylamines (Shimada et al., 1989a).