title: Interindividual variation in biotransformation and cytotoxicity of bromobenzene as determined in primary hepatocyte cultures derived from monkey and human liver.
abstract: 1. Bromobenzene-evoked hepatotoxicity resulting from cytochrome P450-mediated epoxidation has been studied extensively in rodents in vivo and in rodent hepatocytes. In this paper we present data concerning the formation of bromphenols, glutathione (GSH) depletion and cytotoxicity observed in primate hepatocytes in primary culture after exposure to bromobenzene (BrB). 2. After pre-incubation for 2 or 24 h, hepatocytes were exposed to BrB in concentrations up to 2 mM for 4 or 24 h. 3. In both human and cynomolgus monkey hepatocytes BrB cytotoxicity and GSH depletion were found after exposure to 2 mM BrB. The degree of the observed effects was not influenced by the duration of pre-incubation and/or exposure periods. 4. Major inter-individual differences were observed, which could not be attributed to differences in cytochrome P450-mediated bioactivation rates. This suggests that the variation in individual susceptibility to BrB may be related to inter-individual differences in the activity of de-activating (metabolic) pathways. 5. The study of the background of these inter-individual differences may contribute to a more complete understanding of the factors ruling sensitivity to BrB or related chemicals.
authors.affiliation: Research Institute of Toxicology, University of Utrecht, Belgium.
authors.forename: W C
authors.initials: WC
authors.lastname: Mennes
authors.forename: C W
authors.initials: CW
authors.lastname: van Holsteijn
authors.forename: A A
authors.initials: AA
authors.lastname: van Iersel
authors.forename: S H
authors.initials: SH
authors.lastname: Yap
authors.forename: J
authors.initials: J
authors.lastname: Noordhoek
authors.forename: B J
authors.initials: BJ
authors.lastname: Blaauboer
mesh_terms: D000818:Animals; D001711:Biotransformation; D001969:Bromobenzenes / Q000493:pharmacokinetics* / Q000633:toxicity*; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D013045:Species Specificity
chemical_list: D001969:Bromobenzenes; D003577:Cytochrome P-450 Enzyme System; C032036:bromobenzene; D007770:L-Lactate Dehydrogenase; D005978:Glutathione