The AmpliChip CYP450 Test: Principles, Challenges, and Future Clinical Utility in Digestive Disease  Brian D. Juran, Laurence J. Egan, Konstantinos N. Lazaridis  Clinical Gastroenterology and Hepatology  Volume 4, Issue 7, Pages 822-830 (July 2006) DOI: 10.1016/j.cgh.2006.05.002 Copyright © 2006 American Gastroenterological Association Terms and Conditions

Figure 1 Polymorphic drug-metabolizing enzymes. Many drug-metabolizing enzymes responsible for phase I (modification of functional groups) or phase II (conjugation with endogenous compounds) reactions harbor common genetic polymorphisms that potentially affect response to therapy. Those enzymes for which polymorphisms have been shown to alter drug effects are separated from the pie charts. The contribution to phase I and phase II metabolism of drugs of each enzyme is estimated by the relative size of each section. Phase I: ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase; CYP, cytochrome P450; DPD, dihydropyrimidine dehydrogenase; NQO1, NADPH:quinine oxidoreductase or DT diaphorase. Phase II: COMT, catechol O-methyltransferase; GST, glutathione S-transferase; HMT, histamine methyltransferase; NAT, N-acetyltransferase; STs, sulfotransferases; TPMT, thiopurine methyltransferase; UGTs, uridine 5′-triphosphate glucuronosyltransferases. (Reprinted with permission.43 Copyright 1999 AAAS.) Clinical Gastroenterology and Hepatology 2006 4, 822-830DOI: (10.1016/j.cgh.2006.05.002) Copyright © 2006 American Gastroenterological Association Terms and Conditions

Figure 2 Genomic structure of CYP2C19. The CYP2C19 gene, located on chromosome 10 (10q23.33), spans 90,209 base pairs and contains 9 exons (shaded boxes), covering 1473 base pairs and coding for a 491 amino acid peptide. Intervening intron sequences are represented by broken connecting lines, and size is not in scale with the exons. The 2 major allelic variants are shown. The CYP2C19*2 allele harbors the 681 G>A variant, causing a splicing defect resulting in frame shift and premature termination. The CYP2C19*3 allele harbors the 636 G>A variant, causing the creation of a stop codon leading to a truncated protein. Clinical Gastroenterology and Hepatology 2006 4, 822-830DOI: (10.1016/j.cgh.2006.05.002) Copyright © 2006 American Gastroenterological Association Terms and Conditions

Figure 3 Genomic structure of CYP2D6. The CYP2D6 gene located on chromosome 22 (22q13.2) spans 4379 base pairs and contains 9 exons (shaded boxes), covering 1655 base pairs and coding for a 498 amino acid peptide. Intervening intron sequences are represented by connecting lines, and size is shown in scale with the exons. Clinical Gastroenterology and Hepatology 2006 4, 822-830DOI: (10.1016/j.cgh.2006.05.002) Copyright © 2006 American Gastroenterological Association Terms and Conditions

Figure 4 AmpliChip CYP450 predictive phenotypes for CYP2D6. Predicted CYP2D6 metabolic phenotypes based on allelic composition. U: UMs have multiple copies (3 or more) of fully functional alleles (1, 2, or 35) and exhibit excessive metabolic activity. E: EMs carry 1 or 2 fully functional alleles. I: IMs have 1 reduced-activity allele (9, 10, 17, 29, 36, or 41) and 1 null allele (3–8, 11, 14A, 19, 20, or 40). P: PMs carry 2 null alleles and exhibit no CYP2D6 enzymatic activity. Clinical Gastroenterology and Hepatology 2006 4, 822-830DOI: (10.1016/j.cgh.2006.05.002) Copyright © 2006 American Gastroenterological Association Terms and Conditions

Figure 5 Prediction of drug response in the population based on genetic variation. Simple genetic variation in the form of a variant SNP can be used to discriminate between the individuals who will respond favorably to pharmaceutical intervention (black) and those who will have a minor (tan) or major (red) adverse reaction to the treatment. This ability to leverage genetic information to predict ADR will allow physicians to prescribe alternate therapies when available and to identify those in need of more rigorous monitoring when not. Clinical Gastroenterology and Hepatology 2006 4, 822-830DOI: (10.1016/j.cgh.2006.05.002) Copyright © 2006 American Gastroenterological Association Terms and Conditions