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1. The ability of various in vitro systems for CYP enzymes (computer modelling, human liver microsomes, precision-cut liver slices, hepatocytes in culture, recombinant enzymes) to predict various aspects of in vivo metabolism and kinetics of carbamazepine (CBZ) was investigated. 2. The study was part of the EUROCYP project that aimed to evaluate relevant human in vitro systems to study drug metabolism. 3. CBZ was given to the participating laboratories without disclosing its chemical nature. 4. The most important enzyme (CYP3A4) and metabolic route (10,11-epoxidation) were predicted by all the systems studied. 5. Minor enzymes and routes were predicted to a different extent by various systems. 6. Prediction of a clearance class, i.e. slow clearance, was correctly predicted by microsomes, slices, hepatocytes and recombinant enzymes (CYP3A4). 7. The 10,11-epoxidation of CBZ by the recombinant CYP3A4 was enhanced by the addition of exogenous cytochrome-b5, leading to a considerable over-prediction. 8. Induction potency of CBZ was predicted in cultured hepatocytes in which 7- ethoxycoumarin O-deethylase was used as an index activity. 9. It seems that for a principally CYP-metabolized substance such as CBZ, all liverderived systems provide useful information for prediction of metabolic routes, rates and interactions. [ABSTRACT FROM AUTHOR]

1. The construction of a three-dimensional model of human CYP2E1 is reported. It is based on homology with the haemoprotein domain of the unusual bacterial P450, CYP102, which is of known crystal structure. 2. Interactive docking of a number of human CYP2E1 substrates is consistent with their known positions of CYP2E1-mediated metabolism, where specific interactions with key active site amino acid side-chains appear to rationalize the binding and orientation of substrate molecules. 3. Amino acid residues within the putative active site of human CYP2E1, including those associated with the binding of substrates and inhibitors, are shown to correspond with those identified by site-directed mutagenesis experiments conducted on CYP2 family isoforms, and they are known to affect substrate metabolism regioselectivity. 4. Consequently, it was found that the CYP2E1 active site exhibits complementarity with the structural characteristics of known substrates and inhibitors of this enzyme, including their relatively low molecular weights and disposition of hydrogen bond-forming groups. [ABSTRACT FROM AUTHOR]

Of the three isomeric forms of aminobiphenyl, only 4-aminobiphenyl is an established carcinogen while the 2-isomer is considered as a non-carcinogen and 3-aminobiphenyl is at best described as a weak carcinogen. In the present studies we investigated the mutagenicity of these three compounds, their -hydroxy derivatives and their nitrosoderivatives in the Ames test using the strains TA98 and TA100. The studies were performed both in the absence and presence of an activation system derived from the liver of rats pretreated with Aroclor 1254. Of the three isomers only 4-aminobiphenyl exhibited mutagenicity and only in the presence of an activation system. -Hydroxy-4-aminobiphenyl was a potent direct mutagen in both bacterial strains, -hydroxy-2-aminobiphenyl was mutagenic in only TA100 while -hydroxy-3-aminobiphenyl displayed mutagenicity in neither strain. Both 2- and 3-nitrosobiphenyls were direct mutagens in strain TA100. These findings suggest that the weak carcinogenicity of 3-aminobiphenyl may be attributed to the lack of genotoxicity of its -hydroxyderivative, whereas in the case of 2-aminobiphenyl it may be due to the inability of the hepatic preparations to catalyse its -hydroxylation, which is in agreement with published metabolic studies. It is interesting that of the three isomers only 2-aminobiphenyl is non-planar, forming a dihedral angle of 40°, and this may preclude it from acting as a substrate of the P-450I family of haemoproteins, which selectively catalyses the -hydroxylation of many aromatic amines including 4-aminobiphenyl. [ABSTRACT FROM PUBLISHER]