Two Missing Enzymes: Cryopyrin and TPMT – A Hidden Risk for Drug Toxicity

By SWA

In the complex world of human biology, missing just one component can ripple out into life-threatening consequences. In some individuals, two key enzymes—Cryopyrin and TPMT (Thiopurine S-methyltransferase)—are either dysfunctional or entirely absent. While they serve very different roles, the absence of both leads to a dangerous common outcome: inappropriate immune responses and an inability to safely metabolize medications. Together, this creates a risk of piecemeal poisoning, even from standard drug dosages.

1. Cryopyrin: The Guardian of Inflammation

Though not an enzyme in the strict sense, Cryopyrin, encoded by the NLRP3 gene, is a protein that plays a vital role in the innate immune system. It forms part of the inflammasome, a cellular complex that senses internal danger signals and helps regulate inflammation, primarily through the release of interleukin-1β (IL-1β).

When Cryopyrin is missing or mutated, the inflammasome malfunctions. This leads to uncontrolled inflammation, contributing to rare disorders known as Cryopyrin-Associated Periodic Syndromes (CAPS), which include:

In these patients, the immune system reacts too aggressively to minor triggers, or fails to shut down inflammation appropriately, causing chronic symptoms and organ damage.

2. TPMT: The Drug Regulator

Thiopurine S-methyltransferase (TPMT) is a true enzyme—and a critical one. It helps the body metabolize thiopurine drugs, such as:

  • Azathioprine

  • 6-mercaptopurine (6-MP)

  • 6-thioguanine

These medications are used to treat conditions like inflammatory bowel disease, autoimmune disorders, and leukemia. TPMT works by methylating these drugs, which inactivates and clears them from the body.

In patients with TPMT deficiency (due to genetic mutations), the body can’t deactivate the drugs efficiently. The result? The active drug accumulates, damaging rapidly dividing cells like those in the bone marrow. This leads to life-threatening side effects, especially myelosuppression—a dangerous drop in blood cell production.

The Combined Effect: Piecemeal Poisoning

When both Cryopyrin and TPMT are deficient, the body becomes:

  • Hyperreactive to inflammation, even when it's not needed.

  • Unable to clear medications properly, leading to toxic accumulation.

In this setting, a standard dose of a commonly used drug—like azathioprine—can become a relative overdose, poisoning the patient bit by bit. This “piecemeal poisoning” isn’t just limited to thiopurines. The underlying impaired detoxification and immune dysfunction mean that many medications could cause harm, depending on how they are metabolized.

Conclusion

The absence of Cryopyrin and TPMT can turn everyday medications into dangerous toxins. This isn't just a theoretical problem—it's a real concern for individuals with rare genetic variations affecting these proteins. It underscores the importance of genetic testing before starting certain medications, especially thiopurines, and suggests we may need to consider broader screening for patients with unexplained inflammatory or drug toxicity syndromes.

Reference: 

Combined effects of nucleotide-binding domain-like receptor protein 3 polymorphisms and environmental metals exposure on chronic kidney disease
https://pubmed.ncbi.nlm.nih.gov/35428826/

Anti-TNF treatment response in rheumatoid arthritis patients is associated with genetic variation in the NLRP3-inflammasome https://pubmed.ncbi.nlm.nih.gov/24967817/

NLRP3 9 citations Publications for rs4925648
https://www.ncbi.nlm.nih.gov/snp/rs4925648#publications

7 citations Publications for rs7525979
https://www.ncbi.nlm.nih.gov/snp/rs7525979#publications

TPMT 92 citations Missense Variant Publications
https://www.ncbi.nlm.nih.gov/snp/rs1142345


© 2000-2025 Sieglinde W. Alexander. All writings by Sieglinde W. Alexander have a fife year copy right.
Library of Congress Card Number: LCN 00-192742 ISBN: 0-9703195-0-9

Comments

Post a Comment

Popular posts from this blog

Schnitzler Syndrome: A Rare Autoinflammatory Disorder

By SWA
Schnitzler syndrome is a rare, chronic autoinflammatory disease characterized by chronic urticaria (hives), recurrent fever, joint pain, and monoclonal gammopathy (abnormal proteins in the blood). First described by Dr. Liliane Schnitzler in 1972 , this condition is often misdiagnosed, leading to years of untreated symptoms before a correct diagnosis is made. The case report, " A 58-Year-Old Woman With Urticaria, Fever, and Joint Pain " , describes a case that closely aligns with my own experience with this challenging disorder. Key Features of Schnitzler Syndrome Schnitzler syndrome presents with a characteristic set of symptoms, though not all patients experience them in the same way: Chronic Urticaria (Hives) – Persistent, non-itchy or mildly itchy red patches that do not respond to antihistamines. Monoclonal Gammopathy (IgM or IgG type) – Abnormal monoclonal immunoglobulin detected in the blood (most commonly IgM ). Recurrent Fever – Unexplained fever episodes, often...
Read more

Dysferlin Protein: Key Roles, Genetic Locations

By SWA
Image
The purpose of this article is to share and discuss the details of a new discovery, which is highlighted within: CRISPR-Cas9: A Breakthrough Tool to Repair the DYSF Gene The dysferlin protein plays an essential role in maintaining the integrity of muscle cell membranes, particularly in tissues that endure significant mechanical stress, such as skeletal and cardiac muscles . Encoded by the DYSF gene , dysferlin is indispensable for repairing damaged cell membranes after injury caused by muscle contraction or external forces. This article explores the main locations where dysferlin is produced, its role in muscle repair, and supportive nutritional and therapeutic strategies for individuals with dysferlin deficiency, such as those affected by dysferlinopathies (e.g., Limb-Girdle Muscular Dystrophy Type 2B or Miyoshi Myopathy). Currently, there is no definitive answer as to why the severity of dysferlin protein expression or depletion varies. Do pathogens play a role in the methylation o...
Read more

Very Long-Chain Fatty Acids (VLCFAs) X-ALD and Spinal Muscular Atrophy (SMA): Exploring the Connection

By SWA
Update Oct 28th 2024:  A Novel Mouse Model for Cerebral Inflammatory Demyelination in X-Linked Adrenoleukodystrophy: Insights into Pathogenesis and Potential Therapeutic Targets https://onlinelibrary.wiley.com/doi/abs/10.1002/ana.27117 Very Long-Chain Fatty Acids (VLCFAs) are a specific type of fatty acid that are broken down in the body by specialized cellular structures called peroxisomes. These organelles play a critical role in maintaining metabolic balance by degrading VLCFAs. When this process is disrupted, VLCFAs accumulate in various tissues, which can lead to serious metabolic and neurological complications. Elevated VLCFA levels are characteristic of several peroxisomal disorders, most notably X-linked Adrenoleukodystrophy (X-ALD) and Zellweger Syndrome. In X-ALD, for example, a genetic defect impairs the peroxisomal breakdown of VLCFAs, resulting in their accumulation in the brain, spinal cord, and adrenal glands. This buildup can cause progressive neurological damag...
Read more