Factors Affecting Efficacy of Thiopurines for Crohn’s Disease Treatment


Crohn’s Disease is a disease that affects the immune system in which a person’s T cells will attack their GI tract and cause excess inflammation. Treatments for Crohn’s disease have advanced very little in the last decade, even though 3 million Americans are affected by it [1]. The main way Crohn’s is treated is through the use of prescribed thiopurine drugs. These drugs effectively treat many autoimmune disorders by suppressing the immune system, more specifically their capability to inflame certain areas of tissue. In this study, publicly available databases were used to determine what factors may affect the efficacy of thiopurine drugs in certain individuals with Crohn’s disease. First, thiopurine metabolization and how the compounds carried out their function as immunosuppressants were examined, revealing how external factors change the effectiveness of the drug. Then, the role of 6-MP and other thiopurine derivatives in the bile and caffeine pathways were studied, as well as enzymatic disorders that could prevent the drug from being metabolized. Thiopurine enzymes that were likely to have deficiencies resulting in large repercussions were TMPT, XO, IMPD, ITPA, and HPRT. These are important to know to determine someone’s responsiveness to the drug, drug dosage, and if the patient would need any other supplements to keep the pathway functioning. This study concluded that excessive use of compounds or enzymes in the caffeine or bile pathways would detract from the amount available for thiopurine metabolism. Moreover, the outcomes also showed that an enzyme deficiency will likely result in decreased levels of necessary compounds, like 6-MP, that are needed to fully metabolize the drug. Genetic screening is a beneficial solution to prevent enzyme deficiencies from reducing the effectiveness of the thiopurine treatment. This could be used to properly determine the dosage of thiopurines given to a patient so that the treatment is effective while also accounting for the amount of compounds or enzymes available for the body as a whole, including other pathways.


Crohn’s disease is an inflammatory bowel disease (IBD) that causes chronic inflammation in the gastrointestinal (GI) tract. This disease can affect any part of the digestive tract from the mouth to the anus but inflammation is most common at the end of the small intestine (ileum) and beginning of the large intestine. The inflammation can permeate through the thickness of the entire wall. It can also appear in patches through the entire GI tract. It is most often diagnosed in adults between the age of 20 to 30, however, the disease can develop at any age [2]. The direct cause of Crohn’s is still unknown but most studies suggest genetic and environmental factors, like diet or stress, as possible factors. Harmless bacteria in the GI tract are mistaken by the immune system as pathogens and provokes an immune response which causes inflammation [1]. Common symptoms include persistent diarrhea, rectal bleeding, abdominal pain, loss of appetite, weight loss, fatigue, etc [3].

There are many gaps in Crohn’s research currently. There are 5 focus areas that remain under-researched, namely preclinical human IBD mechanisms, environmental triggers, novel technologies, precision medicine, and pragmatic clinical research [4]. Preclinical human IBD mechanisms include research of biochemical pathways, using humanized disease models, to yield novel and effective therapeutic interventions. The specific research gaps include triggers of immune responses, intestinal epithelial homeostasis and wound repair, age-specific pathophysiology, disease complications, heterogeneous response to treatments, and determination of disease location [5]. Precision medicine works to tailor treatments based on specific clinical and biological characteristics of individual patients to deliver optimal care. The main research gaps include understanding and predicting the natural history of IBD (disease susceptibility, activity, and behavior), predicting disease course and treatment response, and optimizing current and developing new molecular technologies [6]. Lastly, the main research gaps within pragmatic clinical research include understanding the epidemiology of IBD, accurate medication selection to increase treatment effectiveness, defining how clinicians are utilizing therapeutic drug monitoring, study of pain management, and understanding the health economics and healthcare resources utilization [7]. All of these questions still need to be answered, just proving how much more research needs to be done to effectively treat Crohn’s disease.

Currently, Crohn’s disease is commonly treated with azathioprine or mercaptopurine, both of which are thiopurines. Thiopurines are immunosuppressive drugs that deactivate the area of T cells which cause inflammation. Once thiopurines enter the body they have to be metabolized to different compounds by different enzymes to create thioguanine [8]. Thioguanine will get incorporated into the DNA of the T cells during DNA replication in place of a guanine nucleotide. This changes the information that the cell receives and gets rid of the inflammation response.


The current issues regarding Crohn’s research is simply that it’s not getting prioritized and that leaves significant gaps in how patients get treated. The objective is to identify how thiopurines aid in the treatment of Crohn’s Disease. Then, this paper will explain why some people with Crohn’s disease respond better or worse to the common thiopurine treatment and how to remedy these issues. This will hopefully go on to help millions of people get access to proper treatments and dosages and incite further research to look for new treatments for Crohn’s.


AZA/6-MP Pathway

The KEGG (Kyoto Encyclopedia for Genes and Genomes) Database was used to identify the intermediates that the drugs azathioprine and mercaptopurine metabolize into before getting incorporated into the T cell DNA [9]. It showed that both compounds existed in the same pathway, “Drug Metabolism- Other Enzymes Reference Pathway” by searching each drug’s pathways individually at first. Figure 1 lists out all the compounds azathioprine is metabolized into and the enzymes that catalyze each reaction. By knowing this, it is easier to see how compounds in the pathway are incorporated in other processes.

Figure 1: Metabolic pathway of AZA. Taken from the KEGG database, and annotated with additional information. The red indicates an enzyme and the black indicates a compound. [10]

Azathioprine (AZA) is turned into 6-Mercaptopurine (6-MP), with the help of glutathione or other endogenous sulfhydryl-containing proteins. This reaction produces 1-Methyl- 4-nitro-imidazole. 6-MP is then further metabolized by three enzymes, thiopurine S-methyltransferase (TPMT), hypoxanthine phosphoribosyltransferase (HPRT), and xanthine oxidase (XO). TPMT adds a methyl group to 6-MP to create 6-methyl-mercaptopurine (6-MMP); XO transfers 6-MP to 6-thiouric acid (6-TUA) and HPRT metabolizes 6-MP into 6-thioinosine monophosphate (6-TIMP). The monophosphate kinase (MPK) enzyme adds a phosphate group to the 6-TIMP to create 6-thioinosine-diphosphate (6-TIDP). Then diphosphate kinase (DPK) transfers it into 6-thioinosine-triphosphate (6-TITP). The inosine triphosphate pyrophosphatase (ITPA) enzyme transfers some of the 6-TITP back into 6-TIMP. Meanwhile, TMPT adds a methyl group to 6-TIMP to create 6-methyl-thioinosine monophosphate (6-MTIMP). Then the MPK and DPK enzymes transfer 6-MTIMP into 6-methyl thioinosine diphosphate (6-MTIDP) and 6-methyl thioinosine triphosphate (6-MTITP). 6-MMP is transferred to 6-MTIMP by HPRT as well. 6-TIMP is also metabolized by inosine monophosphate dehydrogenase (IMPD) to 6-thioxanthosine monophosphate (6-TXMP). 6-TXMP is then transferred to 6-thioguanine nucleotides: 6-TGMP, 6-TGDP, 6-TGTP. Guanosine monophosphate synthetase (GMPS) turns 6-TXMP into 6-thioguanine monophosphate (6-TGMP). 6-TGMP is also metabolized into 6-thioguanine diphosphate (6-TGDP) and 6-thioguanine triphosphate (6-TGTP) by MPK and DPK. Additionally, TPMT adds a methyl group to 6-TGMP to create 6-methyl-thioguanine monophosphate (6-MTGMP) as a byproduct. HPRT converts 6-thioguanine (6-TG) into 6-thioguanine nucleotides while TPMT turns 6-TG into 6-methyl thioguanine (6-MTG) and XO converts 6-TG to 6-thiouric acid (6-TUA). [11]

Figure 2: The process by which 6-TGN, an eventual derivative of thiopurine, causes apoptosis in T-cells.

Figure 3: The process by which the 6-TGTP nucleotide, created from thiopurine metabolism, binds to Rac1 and blocks anti-apoptotic protein and prevents inflammation.

The thioguanine nucleotides (6-TGN) created from the drug are incorporated into the T cell DNA during DNA replication in place of a regular guanine nucleotide. This enacts the mismatch repair system (MMR) to correct the errors in the DNA. However, in this case, the MMR system will work incompletely and results in apoptosis of the T cell. (Figure 2)

When normally functioning, guanine triphosphate binds to the Rac1 gene and the Vav1 protein and the guanine nucleotide exchange factor catalyzes the transformation of Rac1 between GTP (guanine triphosphate) and GDP (guanine diphosphate), in which GTP is active and GDP is inactive. However, when thiopurine drugs are input into the body, thioguanine triphosphate (6-TGTP), one of the three thioguanine nucleotides, binds to Rac1 in place of GTP.

GAP proteins then convert TGTP-bound Rac1 to 6-TGDP-bound Rac1 and Vav1 becomes unable to catalyze the exchange between the two, resulting in the build-up of inactive 6-TGDP-bound Rac1 protein. This decreases inflammation in two ways. First is by apoptosis. Normally, the Vav1 catalyzed activation of the Rac1 gene results in an increased expression of the anti-apoptotic protein Bcl-x, however, the build-up of 6-TGDP-bound Rac1 protein blocks Rac1and prevents Bcl-x formation. Without an anti-apoptotic protein, apoptosis will occur. Second is preventing complex formation between T cells and antigen-presenting cells (APC). Activated Rac1 removes a phosphate group from ezrin-radixin moesin (ERM) proteins in T cells, which leaves room for APC conjugation with a T cell. This process gets reversed when thiopurines prevent activation. If T cells can’t bind to APCs, they can’t enact an immune response, an inflammatory response, to foreign substances because APCs allow T cells to recognize foregin substances. (Figure 3) [12]

Related Compounds/Pathways

After doing a literature search for the thiopurine mechanism of action of Crohn’s disease, the KEGG database was used to identify what other pathways thiopurine intermediates are involved with, under the hypothesis that related pathways may affect drug efficacy or symptoms.

6-MP is also involved in the bile secretion pathway, which was discovered by looking through the substances involved in the highlighted region. (Figure 4)

Figure 4: 6-MP involvement in bile secretion pathway, indicated by compounds/acids highlighted in red. Taken from KEGG Database. [13]

In Figure 4, the red circles marked on the right indicate the location of 6-MP in the pathway. After 6-MP is produced in the thiopurine pathway, some enters the liver to aid in the creation of oleic acid (OA). OA is an antineoplastic, which means that it prevents the abnormal growth of cells to prevent tumors in the liver. This gives the OA some anticancer properties to help protect the liver. However, all antineoplastics have some level of hepatotoxicity, which means that oleic acid is somewhat toxic to the liver. This is why OA must be secreted through urinary output soon after it’s made. If everything functions correctly, the more 6-MP produced, the more oleic acid produced, which could either be excreted or become toxic to the liver. [14]

Looking at the properties of the xanthine oxidase (XO) enzyme in the KEGG Database, it was discovered that XO is also used in the caffeine metabolism pathway (Figure 5). Highlighted in red in Figure 5, XO’s role is to create methyluric acid and dimethyluric acid as more caffeine enters the body. Methyluric acid is a major metabolite of caffeine with antioxidant activity that protects cells from being damaged by unstable atoms [15]. Dimethyluric acid has a role as a human xenobiotic metabolite [16], which means it transforms less polar foreign substances into more polar compounds that can be excreted more easily [17].

Figure 5: Xanthine oxidase (XO) involvement in caffeine pathway, indicated by enzymes highlighted in red. Taken from KEGG Database. [18]

Genes/Proteins + Mutations

In order to identify the diseases or deficiencies that could affect the enzymes involved in the thiopurine pathway, the KEGG database was searched for the properties of each involved in the thiopurine metabolism pathways. The possible diseases and genetic variations that may affect each enzyme were then analyzed.Various additional databases such as Gene Cards were also used to validate these properties, and to understand the possible genetic variations.

Each enzyme also has certain mutations that would affect its function in the thiopurine pathway.


Common Mutation

Helpful Info Link

People Susceptible

Pathway Physiology

Additional Information

Thiopurine S-Methyl Transferase (TPMT)


G238 to C leading to an amino acid substitution at codon 80 (Ala to Pro)

TMPT*3A (having both 3B and 3C):

– 3B= Ala to Thr substitution at codon 154 (G to A first base of codon)

-3C= Tyr to Cys at codon 240 (A to G for second nucleotide in codon) [19]

TMPT*2: Caucasians

TMPT*3A: Caucasians and Southwest Asian [20]

This would cause a significant overproduction of 6-MP and thioguanine because the TMPT cant metabolize these into different compounds.

Name of Disease: TMPT Deficiency (“DISEASE: Thiopurine S-Methyltransferase Deficiency [21]

Xanthine Oxidase (XO)


c.2164A>T (Lys722Ter)

c.682C>T (Arg228Ter)


c.1255C>T (Arg419Ter)

c.169G>C (Ala57Pro)


(go to citation to see complete list of mutations for Xanthinuria)

More common in people with Mediterranean or Middle Eastern ancestry [23]

This defect would cause an over supply of 6-MP which may result in the overproduction of TMPT or another enzyme to help metabolize the 6-MP. If not this, there would be an overproduction of thioguanine.

Name of Disease: Xanthinuria

-low concentration of uric acid in blood and urine [24]

Hypoxanthine Phosphoribosyl Transferase (HPRT)

c.57dup p.Asp20Ter


c.71dup p.Pro25fs


-Over 600 mutations of the HPRT1 gene, located at a q26-27 position on the long arm of the X chromosome


X-linked so males are disproportionately affected [26]

This deficiency would cause a significant decrease in the production of thioguanine because the 6-MP wouldn’t be able to become 6-TIMP. This deficiency would completely disrupt the pathway.

Name of Disease: Lesch-Nyhan Syndrome

-characterized by hyperuricemia with hyperuricosuria and a continuum spectrum of neurological manifestations [27]

Inosine Triphosphate Pyrophosphatase (ITPA)

c.264-607_295 + 1267del1906

c.359_366dupTCAGCACC (p.Gly123Serfs)

c.452G > A (p.Trp151Stop)

c.532C > T (p.Arg178Cys)


Caucasian/Asian populations are more susceptible [28]

This would cause an overproduction of 6-TITP and decrease the 6- TIMP levels which would in turn decrease the thioguanine levels.

Name of Disease: Early Infantile Epileptic Encephalopathy

-characterized by frequent tonic spasms of early onset within a few months of life, and a suppression-burst pattern in electroencephalography (EEG)

-75% of the cases subsequently evolve to West syndrome, and later a much smaller number progress to Lennox-Gastaut syndrome [29]

Inosine Monophosphate Dehydrogenase (IMPD)

Retinitis Pigmentosa:


c.962C>T (p.Ala321Val)

c.959T>C (p.Leu320Pro)

Leber congenital amaurosis:

c.978G>C (p.Gln326His)

c.1598A>G (p.Gln533Arg)

c.1142A>G (p.His381Arg)


(go to citation to see complete list of mutations)

Caucasian/Hispanic/ a few Japanese [31]

Without this enzyme, 6-TIMP wouldn’t be able to become 6-TXIMP. This is the only enzyme that can perform this step of the pathway. Decreased 6-TXIMP would decrease thioguanine levels.

Name of Disease: Retinitis


-peripheral vision loss and night vision difficulties

-comorbid diseases of syndromic RP are Usher syndrome and Bardet-Biedl syndrome [32]

Name of Disease: Leber congenital amaurosis

-affected infants have little or no retinal photoreceptor function as tested by electroretinography [33]


Significance of Related Pathways

The possible relationship between thiopurine metabolism and the pathways in which thiopurine intermediates existed were examined, primarily the bile secretion pathway and caffeine pathway.

The bile secretion pathway would be affected by a change in 6-MP levels. An increase in 6-MP levels may cause hypertoxicity in the liver because of an increase in antineoplastics. This may cause the liver to fail or a plethora of other hepatic diseases. This increase in 6-MP levels is likely if the patient has TMPT deficiency or Xanthinuria, which is why making sure the Crohn’s patient gets the right dosage is crucial. It is confirmed that a TPMT deficiency can cause an increase in toxicity when treated with thiopurines [34]. If 6-MP levels decrease, there may be an increase likelihood of developing a hepatic tumor, however, this is unlikely because there are a lot of other antineoplastics that are also in the the liver, which means they could serve in place of 6-MP in the instance that the levels decrease. This is why there is always a delicate balance of how much of the drug to dose a patient.

As seen in the caffeine diagram above, the XO enzyme is used to make different acids such as methyluric acid and dime thyluric acid. One conclusion drawn from this diagram is that the more caffeine that enters the body, the more XO needed to create these enzymes and keep the pathway functioning. Therefore, in the instance that the body did not respond by overexpressing the enzyme, an increased caffeine consumption in a patient with Crohn’s Disease would reduce the effectiveness of the medication because less XO would be available to perform its function in the thiopurine pathway. This may lead to a build up in 6-MP which would either create build ups of different compounds or, if the enzymes were upregulated, would create more thioguanine nucleotides, which would speed up the process for dismantling the T cells. Certain genetic variants might also have an effect on the caffeine and thiopurine pathways, especially if the patient has Crohn’s. For example, if a patient has xanthinuria, they may want to reduce caffeine consumption because they would already have a deficiency and they soul conserve the XO enzyme to work in the thiopurine pathway. It has been proven that a complete XO deficiency can cause severe toxicity with a full dose of AZA [35]. Another example would be if the patient has TMPT deficiency, they would already be producing an oversupply of 6-MP and would need more of the XO enzyme, which is another reason to reduce caffeine consumption.

Genetic Screening

Because of the many common mutations that may affect thiopurine metabolism, screening for the mutations listed above could dramatically improve dosing of azathioprine/mercaptopurine for Crohn’s disease patients. The aforementioned deficiencies could either increase or decrease the production of thioguanine, which means either more or less of the drug needs to be administered to maximize the effectiveness of the drug. Some candidate screening technologies include microarrays, polymerase chain reactions (PCRs), and DNA sequencing. Microarrays look at all of the chromosomes at once. They contain thousands of short, single stranded DNA that is attached to a chip. The human DNA is then compared to the normal microarray to determine any duplications, deletions, etc. PCRs make copies of numerous short DNA sections from a small sample of genetic material that can later be analyzed and sequenced to determine variants. DNA sequencing will determine the order of the base pairs that make up DNA. This allows scientists to look for a specific variant or mutation to find a disorder. [36] To improve treatment of Crohn’s disease, these tests should always be used to detect the certain mutations/variants listed above to let a physician know if there is an enzyme deficiency before administering a drug so as to not do more harm to the patient. For example, if the patient had an IMPD, ITPA, or HPRT deficiency that meant a lot of the drug would not get metabolized into thioguanine, the physician would either need to change the drug dosage or if possibly supplement the enzymes to make the pathway efficient. In fact, multiple groups with an ITPA variation correlates with increased toxicity to thiopurines [28]. Screening gives the doctor or person prescribing the dosage of thiopurine drugs a much clearer picture of how much to give the patient to ensure that there aren’t any ramifications, within the thiopurine pathway or another pathway it connects to, that they would have missed otherwise.

Future research could go on to find different, more accurate screening methods to ensure the safety of patients. There is also a need for more research into how compound or enzyme levels are affected by other pathways and mutations. A lot has been hypothesized but more quantifiable evidence could be found. For example, a certain percentage of enzyme deficiency would lead to a certain percentage of 6-MP increase. This would create a much more streamlined system of dosing patients with Crohn’s.


Through literature searches and using a collection of databases, several possible mechanisms that may cause Crohn’s disease patients to have different responses to thiopurines have been identified. The bile secretion pathway and the caffeine metabolism pathway have a complex relationship with thiopurine metabolism that potentially affect the biochemical rates of reactions in the thiopurine metabolism pathway. Additionally, many common genetic variants play a potential role in thiopurine metabolism and response. Small molecules could be used to better regulate the bile secretion and caffeine metabolism pathways in the presence of thiopurine, and genetic screening to improve dosing for patients with genetic variants. Of course, both of these areas will need to be researched deeply before such therapies could be administered to a patient, but this research can help start the conversation about how to improve personalized medicine for Crohn’s disease patients.


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National Institute of Diabetes and Digestive and Kidney Diseases. 2019. “Antineoplastic Agents.” In LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda, MD: National Center for Biotechnology Information.

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Common Mutation Helpful Information

A- adenine

G- guanine

C- cytosine

T- thymine

Codon- 3 nucleotides that form a specific genetic code in DNA or RNA that codes for an amino acid, which will go on to create proteins










































































A mutation in which a nucleotide is replaced, added, or deleted can result in a change in its genetic code.

How to Read Mutation Notation:

ex) 169G>C (Ala57Pro)

  • Codon 169 originally had G (guanine) but a mutation replaced G with C (cytosine). This changes the amino acid created from Ala to Pro.

ex) c.452G > A (p.Trp151Stop)

  • Codon 452 originally had G (guanine) but a mutation replaced G with A (adenine). This changes the amino acid created from Trp to an ending sequence for the chain of amino acids that would have been created.

About the author

Eesha Bethi is currently a junior at Carroll Senior High School in Southlake, Texas. She has always been interested in STEM fields, specifically molecular biology, and hopes to pursue a career in medicine in the future. Mixed with her interest in autoimmune diseases, this started the basis of her research. She also enjoys humanitarian volunteer activities and public speaking. 

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