PubMed Health⌕ Search
Home/Archive/PubMed

PubMed · 10723863

Pharmacogenetics.

C R Wolf·G Smith
View original source ↗Export metadata ↓

Abstract

Inter-individual variability in drug response is a major clinical problem. Adverse drug reactions (ADRs) are common, are responsible for a number of debilitating side effects following drug therapy and are a significant cause of death. It is now clear that much of the observed variability in drug response has a genetic basis, arising as a result of genetically-determined differences in drug absorption, disposition, metabolism or excretion. The best characterised pharmacogenetic polymorphisms are those within the phase I cytochrome P450 family of drug metabolising enzymes. One of these enzymes, CYP2D6 (debrisoquine hydroxylase), metabolizes one-quarter of all prescribed drugs and is inactive in 6% of the Caucasian population. Individuals at risk of developing ADRs as a result of genetically-determined variation in genes such as CYP2D6 can now be identified using DNA-based tests. A detailed knowledge of the genetic basis of individual drug response is potentially of major clinical and economic importance and could provide the basis for a rational approach to drug prescription. This would have significant benefits for human health.

Explore related subjects

Cytochrome P-450 Enzyme SystemHumansPharmaceutical PreparationsPharmacogeneticsPolymorphism, GeneticRacial GroupsJournal ArticleResearch Support, Non-U.S. Gov'tReview

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

C R Wolf, G Smith. 1999. Pharmacogenetics.. https://doi.org/10.1258/0007142991902439

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related citations

PubMed2025

Inference of Cytochrome P450 Evolutionary History Using Structural and Physicochemical Metrics.

Cytochrome P450s are a superfamily of heme-binding monooxygenases involved with the detoxification of intrinsic and extrinsic toxins. They are near ubiquitous within biological domains and are found in all domains. Members of families within the superfamily are defined based on amino acid identity thresholds, with thresholds as low as 40% in some families. Relationships among Cytochrome P450 families have proven elusive due to sub-Twilight Zone interfamily identities (<30%) that result in poor multiple sequence alignment quality and thus low levels of support for downstream phylogenetic reconstructions. Despite the low identities, Cytochrome P450 structures are remarkably well conserved both within and among families. In such cases, structural phylogenetics has the potential to unveil elusive relationships because the selectively favored physicochemical properties giving rise to the structure and function of the proteins persist despite sequence-level divergence. Recently, in two separate publications, we demonstrated that by utilizing physicochemical vectors, dynamic time warping, and hierarchical clustering (PCDTW), large swaths of protein domain families and betacoronavirus receptor-binding domain clades were congruent with validated functional/structural relationships. These were important findings because anomalous sequence alignment-based maximum likelihood phylogenetic findings, which were not congruent with the known functional relationships, were resolved. That also validated the use of physicochemical vectors in making inferences about structural/functional homology. Additionally, it illuminated that the same methods might be applied to other protein families with relationships that are difficult to resolve from sequence data alone. Herein, we used Molecular Weight and Hydrophobicity Physicochemical Dynamic Time Warping (MWHP PCDTW) along with structural and sequence alignment-based phylogenetic methodologies to analyze all of the Cytochrome P450s found both in the high-fidelity Structural Classificaction of Proteins (SCOP) database and the reviewed sequences with both experimentally resolved and de novo predicted structures in the Protein Data Bank and the AlphaFold (AF) Protein Structure Database, respectively. We compared the resulting phylogenetic topologies and found that in some cases, structure-based methods may be less able to resolve random/convergent similarity than physicochemical and sequence-based methodologies. This finding agrees with previous findings that demonstrate the usefulness of physicochemical properties in resolving both random structural similarity and potentially convergent relationships.

Cytochrome P-450 Enzyme System↗
PubMed2003

Can a single oxidant with two spin states masquerade as two different oxidants? A study of the sulfoxidation mechanism by cytochrome p450.

Density functional calculations were performed on the sulfoxidation reaction by a model compound I (Cpd I) of cytochrome P450. By contrast to previous alkane hydroxylation studies, which exhibit a dominant low-spin (LS) pathway, the sulfoxidation follows a dominant high-spin (HS) reaction. Thus, competing hydroxylation and sulfoxidation processes as observed for instance by Jones et al. (Volz, T. J.; Rock, D. A.; Jones, J. P. J. Am. Chem. Soc. 2002, 124, 9724) are the result of a two-state reactivity scenario, whereby the hydroxylation originates from the LS pathway and the sulfoxidation from the HS pathway. In this manner, two spin states of a single oxidant (Cpd I) can be disguised as two different oxidants. The calculations rule out the possibility that a second oxidant (the ferric peroxide, Cpd 0 species) interferes in the observed results of Jones et al.

Cytochrome P-450 Enzyme System↗
PubMed2003

The invasive phenotype of Shigella flexneri directs a distinct gene expression pattern in the human intestinal epithelial cell line Caco-2.

Invasion of the human colonic epithelium by Shigella flexneri causes inflammation that disrupts the intestinal barrier. Invaded intestinal epithelial cells are the major source of mediators recruiting the inflammatory infiltrate. To better characterize the global response of intestinal epithelial cells to Shigella invasion, Caco-2 cells were infected by an invasive isolate of S. flexneri 5a, and their transcriptome was analyzed by Affymetrix (Santa Clara, CA) microarrays (12,000 genes) and compared with these elicited by a non-invasive Shigella mutant and tumor necrosis factor (TNF)-alpha. The invasive and non-invasive strains enhanced transcription of a common pattern of 240 genes, among which genes encoding isoforms of cytochrome P-450 were induced. These genes were not induced by TNF-alpha. Conversely, both the invasive strain and TNF-alpha induced a common set of 18 genes, mainly encoding proinflammatory molecules. They also induced specific sets of genes. The transcriptome induced by the invasive strain was characterized by the induction of early genes (i.e. expressed within the first 45 min of invasion) and late genes (i.e. after 60 min of invasion) whose pattern was strongly biased toward stimulation of granulopoiesis, chemoattraction, activation, and adherence of polymorphonuclear leukocytes. When compared with a non-invasive Shigella and TNF-alpha, invasive Shigella induced a narrow transcriptome that seems to program infected epithelial cells to recruit a mucosal polymorphonuclear leukocyte to infiltrate. Dramatic increase in IL-8 gene transcription points to this chemokine as the major molecule orchestrating mucosal inflammation in shigellosis.

Cytochrome P-450 Enzyme System↗