Genetic variation in the human hepatic cytochrome P-450 system

Abstract

Studies in rodents indicate that the cytochrome P-450 system consists of a superfamily of heme proteins, produced by clusters of structural genes on different chromosomes. Equivalent P-450s of different species show more homologies than members of different P-450 families within a species. The Ah receptor serves the induction of members of one of the cytochrome families. The human structural gene for the methylcholanthrene-inducible P1-450 is located on Chromosome 15. This gene has been completely sequenced. The human Ah receptor is also measurable. New methods to measure inducibility in man involve new lymphocyte bioassays and mRNA determinations, while in vivo biotransformation studies of caffeine allow estimates of the state of induction. Structural genes for phenobarbital-inducible cytochromes have been localized to Chromosome 19. The deficiency of biotransformation of debrisoquine and sparteine continues to be explored intensely. Linkage studies indicate the gene for the variable cytochrome P-450 to be located on Chromosome 22. The deficiency is more likely due to structural variation than absence of the cytochrome. Inhibiting drugs can mimic the genetic defect. Many pharmacological and toxicological consequences of the deficiency have been defined. The main characteristics of the genetic deficiencies affecting the metabolisms of mephenytoin, phenytoin, tolbutamide, nifedipine and of methyl cysteine were outlined briefly.