Pharmacogenomics in Inflammatory Bowel Disease Laurence J. Egan, Luc J.J. Derijks, Daniel W. Hommes  Clinical Gastroenterology and Hepatology  Volume 4, Issue 1, Pages 21-28 (January 2006) DOI: 10.1016/j.cgh.2005.10.003 Copyright © 2006 American Gastroenterological Association Terms and Conditions

Figure 1 Mechanisms of pharmacogenetics. Pharmacokinetic factors (left) affect the concentration of drug at the active site. In the example, an individual inherits 2, 1, or none of the wild-type (WT) alleles of the TMPT gene, along with none, 1, or 2 of the mutant (Mut) inactive alleles. This provides TPMT activity that is normal, intermediate, or low (absent), which is accompanied by low, intermediate, or high active thiopurine drug levels. Therefore, AZA or 6-MP active metabolite levels are greater in the presence of mutant alleles, with a much greater chance of toxicity. Pharmacodynamic factors (right) do not affect drug concentration but often affect the expression or activity of the drug’s target, in this example gefitinib, which inhibits the epidermal growth factor receptor (EGFR). Certain tumors, such as lung cancer and possibly colon cancer, select for mutant EGFR that is constitutively overactive, which provides a growth or survival advantage to those cells. EGFR inhibitor produces a therapeutic effect in the presence of the mutant overactive EGFR, whereas WT EGFR, which has little constitutive activity, is not greatly affected by the inhibitor. Clinical Gastroenterology and Hepatology 2006 4, 21-28DOI: (10.1016/j.cgh.2005.10.003) Copyright © 2006 American Gastroenterological Association Terms and Conditions

Figure 2 Pathways of thiopurine metabolism. The positions of 2 polymorphically expressed enzymes, TPMT and ITPA, are shown. 6-TIMP, 6-thio inosine monophosphate; 6-TIDP, 6-thio inosine diphosphate; 6-TITP, 6-thio inosine trinophosphate; 6-TG, 6-thioguanine (nucleotides). Arrows indicate a pathway of metabolism and bar indicates inhibition of purine production. Clinical Gastroenterology and Hepatology 2006 4, 21-28DOI: (10.1016/j.cgh.2005.10.003) Copyright © 2006 American Gastroenterological Association Terms and Conditions

Figure 3 TPMT genotypes. The black and white boxes represent translated and untranslated exons, respectively. The gray boxes represent translated exons on mutant alleles containing an SNP, which is captioned below the relevant exon. Clinical Gastroenterology and Hepatology 2006 4, 21-28DOI: (10.1016/j.cgh.2005.10.003) Copyright © 2006 American Gastroenterological Association Terms and Conditions