Saleh AlAbdulhadi

Pharmacogenetis as gene and stem-cell therapies Dr. Saleh Al-Abdulhadi What is pharmacogenetics • It is the study of differences in drug response due to allelic variation in genes affecting drug metabolism, efficacy, and toxicity. • The variations drug response is in two ways: pharmacokinetics, and pharmacodynamics. • Pharmacokinetic variations • An example of this variation include polymorphic alleles in the cytochrome P450 system. • Human cytocrome P450 proteins are large family of 56 different enzymes, each encodeded by a different CYP gene. • This proteins are hem-containing proteins in livers, the heme Fe2+ allows them to accept electrons donors, and use them to catalyzing number of different reactions. • This action of Cytochrome P450 and exchange atoms by adding hydroxyl group to the molecule know as the phase I of drug metabolism. • In Phase II, the added hydroxyl group provide a site for sugar or acetyl group to be attached to the drug. • Cytochrome P540 are classified into 20 families according to amino acid sequences. • Based on variation and classification, There are 3 main recognized phenotypes: • (1) Normal metabolizers, (2) poor metabolizers, (3) ultrafast metabolizers. • Patients with Poor metabolizers phenotype are at risk of accumulation of toxic levels of drug. • Patients with ultrafast metabolizers phenotype are at risk for being undertreated with doses inadequate to maintain blood levels in the therapeutic range. • Phase II: the main important steps are glucuronidation by UDP- glycosyltransferase and acetylation by N-acetyltransferase. Example: polymorphism in N-acetyltransferase gene, associated with slow and rapid inactivation for drug used in isoniazid therapy for tuberculosis. Variations in pharmacodynamic • Deficiency of G6PD enzyme are clinically susceptible to drug-induce hemolysis. • Example: 1) oxidant drug such as primaquine deplete the cells of reduced glutathione and consequent oxidative damage leads to hemolysis. 2) malignant hyperthermia, gene associated disease is RYR1 encodes an intracellular calcium ion channel. This condition is an important cause of death during OR. Stem-cell therapy • Modification of the somatic genome. • Transplanted cells retain the genotype of the donor. • Stem cell transplant: stem cells a re self renewing cells definded by two properties: 1) ability to proliferate to form the differentiated cell types of tissue in vivo, 2) ability to self renew to form another stem cell. • Only two types of stem cells are in clinical use: 1)hematopoietic stem cells, which can reconstitute the blood system after bone marrow transplantation, 2) corneal stem cells, which are used to regenerate the corneal epithelium. • 1)hematopoietic stem cell transplantation for lysosomal storage disease: 1) transplantation from bone marrow: • Bone marrow stem cells transplant are effective in correcting lysosomal storage in many tissues included. The transplanted cells are a source of lysosomal enzymes that can be transferred to other cells through the extracellular fluid. Bone marrow derived cells consist 10% of body cell with high quantities of the enzyme. • Examples: Hunter syndrome, Krabbe disease, Gaucher disease. 2) Transplantation from placental cord blood: placental cord blood is a rich source of hematopoietic stem cells. It has 3 main advantages: 1) recipients are more tolerate of histoincompatible placental blood than other allogeneic donor cells. 2) wide availability of placental cord blood together with tolerantly expands number of donor. 3)risk of graft versus host disease is substantially reduced with use of placental cord blood Examples: hurler syndrome, neonatal form of krabbe disease, Glossary: • • • • • • • • Pharmacogenetics Pharmacokinetics Pharmacodynamics Cytochrome P450 Normal metabolizers Poor metabolizers Ultrafast metabolizers N-acetyltransferase • Pharmacogenetics • Deficiency of G6PD enzyme • Stem-cell therapy • lysosomal storage disease • hematopoietic stem cell transplantation • placental cord blood transplantation