Pharmacogenetics of drug-metabolizing enzymes: implications for a safer and more effective drug therapy

Abstract

The majority of phase I- and phase II-dependent drug metabolism is carried out by polymorphic enzymes which can cause abolished, quantitatively or qualitatively decreased or enhanced drug metabolism. Several examples exist where subjects carrying certain alleles do not benefit from drug therapy due to ultrarapid metabolism caused by multiple genes or by induction of gene expression or, alternatively, suffer from adverse effects of the drug treatment due to the presence of defective alleles. It is likely that future predictive genotyping for such enzymes might benefit 15-25% of drug treatments, and thereby allow prevention of adverse drug reactions and causalities, and thus improve the health of a significant fraction of the patients. However, it will take time before this will be a reality within the clinic. We describe some important aspects in the field with emphasis on cytochrome P450 and discuss also polymorphic aspects of foetal expression of CYP3A5 and CYP3A7.

Figure 1

Active P450 genes in the human genome. The different families of P450 in humans are represented by vertical lines, those of families 1–3 are enzymes involved in xenobiotic metabolism, while those in higher families metabolize endogenous substrates. The subfamilies are represented by a letter and isoforms are followed by an Arabic number.

Figure 2

(a) Rate of alprazolam 4- and 1-hydroxylation by human foetal liver microsomes homozygous for CYP3A7*2/CYP3A5*1 when compared to CYP3A7*1/CYP3A5*3 foetal liver. 4OH-alprazolam is produced by CYP3A7 and CYP3A5, alprazolam 1-hydroxylation is mainly catalysed by CYP3A5. Data from Rodriguez-Antona et al. 2005b. FLM, foetal liver microsomes; 4OH-Alpr, 4-hydroxy alprazolam; 1OH-Alpr, 1-hydroxy alprazolam. (b) Structure of CYP3A7-3AP1 mRNA and CYP3A7.1L protein. The rectangles represent part of the coding region of CYP3A7-3AP1, specifically, the last 3 exons from the 15 exons full transcript encoding the novel carboxy-terminal sequence of CYP3A7.1L are shown. The arrows indicate the splicing junctions. Intronic sequences are shown in lower case, and the polymorphism abolishing the pseudogene splicing is indicated by a start and the possible nucleotides within brackets (CYP3A7_39256 T>A). CYP3A7.1L has been characterized in Rodriguez-Antona et al. (2005b).

Figure 3

(a) Human cytochrome P450 family 3. The human CYP3A locus is located on chromosome 7q21–q22.1 and contains four genes: CYP3A4, CYP3A5, CYP3A7 and CYP3A43, and three pseudogenes: CYP3AP1, CYP3AP2 and CYP3AP3. The linkage disequilibrium between functional SNPs in this region results in different common CYP3A haplotypes that have pronounced interethnic differences. The developmental regulation of the CYP3A genes in combination with the different alleles result in the expression of different sets of CYP3A enzymes. (b) Common CYP3A haplotypes. The two most frequent haplotypes that result in expression of different sets of CYP3A enzymes are depicted. The frequencies estimated in Caucasians and Africans are shown. In Caucasians the most common allele combination is: CYP3A7*1/CYP3A7_39256 T/CYP3A5*3 which results in the expression of CYP3A7.1 and CYP3A7.1L proteins. In Africans the most frequent allele combination is: CYP3A7*2/CYP3A7_39256 A/CYP3A5*1 resulting in the expression of CYP3A7.2 and CYP3A5 proteins.