Pharmacogenetics in inflammatory bowel disease

Abstract

Pharmacogenetics is the study of the association between variability in drug response and (or) drug toxicity and polymorphisms in genes. The goal of this field of science is to adapt drugs to a patient's specific genetic background and therefore make them more efficacious and safe. In this article we describe the variants in genes that influence either the efficacy or toxicity of common drugs used in the treatment of inflammatory bowel diseases (IBD), ulcerative colitis (UC), and Crohn's disease (CD) including sulfasalazine and mesalazine, azathioprine (AZA) and 6-mercaptopurine (6-MP), methotrexate (MTX), glucocorticosteroids (CSs) and infliximab. Furthermore, difficulties with pharmacogenetic studies in general and more specifically in IBD are described. Although pharmacogenetics is a promising field that already contributed to a better understanding of some of the underlying mechanisms of action of drugs used in IBD, the only discovery translated until now into daily practice is the relation between thiopurine S-methyltransferase (TPMT) gene polymorphisms and hematological toxicity of thiopurine treatment. In the future it is necessary to organize studies in well characterized patient cohorts who have been uniformly treated and systematically evaluated in order to quantitate drug response more objectively. An effort should be made to collect genomic DNA from all patients enrolled in clinical drug trials after appropriate informed consent for pharmacogenetic studies.

Figure 1

Simplified scheme of AZA metabolism: AZA is non-enzymatically converted to 6-MP. 6-MP is converted into the 6-thioinosine monophosphate (6-TIMP) by the enzyme hypoxanthine guanine phosphoribosyl-transferase (HGPRT). 6-TIMP is further metabolized to thioguanine mono, di and triphosphates [6-thioguanine nucleotides (TGN)]. Alternatively 6-MP can be inactivated by xanthine oxidase (XO) into 6-thiouric acid (6-TU) or by TPMT into 6-methylmercaptopurine (6-MMP). TPMT also catalyses the methylation of the nucleotide metabolites including 6-TIMP and 6-thioguanosine-5’-monophosphate to 6-methylmercaptopurine (6-MMPR). Inosine monophosphate dehydrogenase (IMPDH) and guanine monophosphate synthetase (GMPS). Inosine triphosphate pyrophosphatase (ITPA), 6-thioinosine triphosphate pyrophosphate (6-TITP).

Figure 2

The dotted arrows indicate inhibitory effects of MTX methotrexate. RFC1 reduced folate carrier 1; MTXglu methotrexate polyglutamate; AICAR, 5-aminoimidazole-4-carboxamide ribonucleotide; DHF, dihydrofolate; THF, tetrahydrofolate; dhfr, dihydrofolate reductase; mthfr, methylene tetrahydrofolate reductase; 5,10-CH-THF, 5,10 methenyl THF; 5,10-CH2 THF, 5,10 methylene THF; 10-CHO THF, 10-formyl THF; Hcy, homocysteine; 5-CHO THF, 5-formyl THF; ms, methionine synthetase; Met, methionine; SAM, S-adenosyl-L-methionine; R, methyl acceptor; SAH, S-adenosyl–L-homocysteine.

Figure 3

Anti-inflammatory mechanism of glucocorticoids (CSs). CSs enter the cell and interact with the glucocorticoid receptor (GRα) to change the GR conformation, induce formation of GR homodimers and translocation to the nucleus. GR homodimers specifically bind to glucocorticoid response elements (GRE) in target genes. HSP90, 90-kDa heat shock protein; HSP70, 70-kDa heat shock protein; IP, 56-kDa immunophilin; IκBα inhibitor kappa B alpha; NF-κB, nuclear factor kappa B; AP-1, activator protein 1.