Mapping determinants of the substrate selectivities of P450 enzymes by site-directed mutagenesis

Article Abstract:

The factors determining substrate selectivities of cytochrome P450 monooxygenases were identified in point-mutation studies. Site-directed mutagenesis of P450 enzymes revealed key residues that may be responsible for the catalytic properties of cytochrome P450. These key residues are in sites that map to amino acids forming the P450cam substrate-binding site. The sites in P450cam allow genetic variation without enzyme topology disruption. This may account for the structural and catalytic diversity in mammalian P450 enzymes.

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Interethnic variation of drug metabolism

Article Abstract:

The presence of drug-metabolizing enzymes such as aldehyde dehydrogenase and debrisoquine hydroxylase in the body varies in relation to ethnic origins. Genetic differences do not account for all the observed interethnic variation in drug utilization and elimination pathways. The occurrence of allelomorphism explains some of the drug metabolic responses identified in certain ethnic groups. However, the exact cause of drug metabolism variation remains unidentified and requires further studies.

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Transgenic xenosensors: humanizing mice

Article Abstract:

Researchers have succeeded in creating a mouse model for the up-regulation of the cytochrome P450 enzyme CYP3A4. These mice develop CYP3A4 up-regulation in the presence of human CYP3A4 inducers.

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