The carcinoGENOMICS project: Critical selection of model compounds for the development of omics-based in vitro carcinogenicity screening assays

Recent changes in the European legislation of chemical-related substances have forced the scientific community to speed up the search for alternative methods that could partly or fully replace animal experimentation. The Sixth Framework Program project carcinoGENOMICS was specifically raised to develop omics-based in vitro screens for testing...

Uniform procedure of 1H NMR analysis of rat urine and toxicometabonomics Part II: Comparison of NMR profiles classification of hepatotoxicity

A procedure of nuclear magnetic resonance (NMR) urinalysis using pattern recognition is proposed for early detection of toxicity of investigational compounds in rats. The method is applied to detect toxicity upon administration of 13 toxic reference compounds and one nontoxic control compound (mianserine) in rats. The toxic compounds are...

A sandwich-cultured rat hepatocyte system with increased metabolic competence evaluated by gene expression profiling

A rapid decline of cytochrome P450 (CYP450) enzyme activities remains a drawback of rat hepatocyte-based in vitro cultures. Consequently, judgment of the toxic potential of compounds that need bioactivation by CYP450s may not be adequate using this model. In the present study, an improved hepatocyte-based in vitro system was developed with...

Comparison of coumarin-induced toxicity between sandwich-cultured primary rat hepatocytes and rats in vivo: A toxicogenomics approach

Sandwich-cultured primary rat hepatocytes are often used as an in vitro model in toxicology and pharmacology. However, loss of liver-specific functions, in particular, the decline of cytochrome P450 (P450) enzyme activity, limits the value of this model for prediction of in vivo toxicity. In this study, we investigated whether a hepatic in vitro...

Characterization of cytochrome P450 isoenzymes in primary cultures of pig hepatocytes

Despite the fact that pigs are increasingly used in pharmacological and toxicological studies, knowledge on the enzymes which metabolize xenobiotics, in particular cytochrome P450 (CYP) enzymes, in pigs is still very limited. Primary cultures of pig hepatocytes were used to characterize CYP enzymes. The characterization was performed at the...

Increased bioactivation of dihaloalkanes in rat liver due to induction of class Theta glutathione S-transferase T1-1

A characteristic feature of the class Theta glutathione S-transferase (GST) T1-1 is its ability to activate dichloromethane and dibromoethane by catalysing the formation of mutagenic conjugates. The level of the GSTT1 subunit within tissues is an important determinant of susceptibility to the carcinogenic effects of these dihaloalkanes. In the...

Species and strain differences in the hepatic cytochrome P450-mediated biotransformation of 1,4-dichlorobenzene

Our goal was to characterize possible species and strain differences in the hepatic microsomal biotransformation of 1,4-dichlorobenzene (1,4-DCB). Experiments compared extent of labeled 1,4-DCB conversion to oxidized metabolites, glutathione conjugates, and covalently bound metabolites by hepatic microsomes from humans, from male B6C3F1 mice,...

Rat liver microsomal cytochrome P450-dependent oxidation of 3,5-disubstituted analogues of paracetamol

1. The cytochrome P450-dependent binding of paracetamol and a series of 3,5-disubstituted paracetamol analogues (R = -F, -Cl, -Br, -I, -C(H)3, -C2H5, -iC3H7) have been determined with β-naphthoflavone (βNF)-induced rat liver microsomes and produced reverse type I spectral changes. K(s,app) varied from 0.14 mM for 3,5-diiC3H7-paracetamol to 2.8...

Differences in cytochrome P450-mediated biotransformation of 1,2- dichlorobenzene by rat and man: Implications for human risk assessment

The oxidative biotransformation of 1, 2-dichlorobenzene (1, 2-DCB) was investigated using hepatic microsomes from male Wistar, Fischer-344 and Sprague-Dawley (SD) rats, phenobarbital (PB)- and isoniazid (ISO) pretreated male Wistar rats and from man. In addition, microsomes from cell lines selectively expressing one cytochrome P450 (P4502E1, 1A1...

Dose-dependent kinetics and metabolism of 1,2-dichlorobenzene in rat: Effect of pretreatment with phenobarbital

Toxicity of halobenzenes has been ascribed mainly to their epoxides, but recent studies with bromobenzene have shown that secondary quinone metabolites are also involved in the alkylation of hepatic proteins. However, the relative contribution of the quinones and the epoxides to the toxicity of halobenzenes is still unclear. In order to...

The influence of aging on the metabolism of simultaneously administered hexobarbital enantiomers and antipyrine before and after phenobarbital induction in male rats: A longitudinal study

The influence of aging on the metabolism of antipyrine (AP) and hexobarbital enantiomers (R-HB and S-HB) with and without phenobarbital (PB) induction was investigated in a longitudinal study in rats aged 6, 12, 24 and 30 months. The metabolic clearances of AP (Cl(m AP)), R-HB (Cl(m R-HB)) and S-HB (Cl(m S-HB)) were used as indicators for P450...

The effect of age on inducibility of various types of rat liver cytochrome P-450

The content and specific activities of inducible cytochrome P-450 enzymes were determined in liver microscomes of rats of various ages after maximal induction with phenobarbital, isosafrole of 3-methylcholanthrene, and in untreated animals. With age an increase in liver weight was observed both in untreated rats and in maximally induced ones;...

The relation between the oxidative biotransformation of hexachlorobenzene and its porphyrinogenic activity

The relation between the major toxic effect of hexachlorobenzene, hepatic porphyria, and its oxidative biotransformation was studied in vivo, by observing the effect of modulating its biotransformation on the expression of porphyria. This modulation was achieved by selective in vivo inhibition of the major cytochrome P450 isoenzyme involved in...