1-Methyl-4-nitrosopiperazine

1-Methyl-4-nitrosopiperazine

 

• CAT Number : Gly-GMSI-108
• CAS Number : 16339-07-4
• Molecular Weight : 129.16
• Molecular Formula : C₅H₁₁N₃O
• Pack size: 0.1 g

Product Description
1-Methyl-4-nitrosopiperazine (MNP) is a chemical compound with the molecular formula C₅H₁₁N₃O. It is a nitroso derivative of methylpiperazine.

Property
MNP has a molecular weight of 129.16 g/mol. It is a solid compound at room temperature.

Application and Usage
1-Methyl-4-nitrosopiperazine is primarily used as an analytical standard in research and chemical analysis. It is often employed in the study of nitrosamine compounds and their effects.

Safety and Handling
Handle with caution as nitrosamine compounds can be potentially harmful. Use appropriate personal protective equipment and follow standard safety protocols for chemical substances. Store according to manufacturer's recommendations.

Involved Human Diseases

1-Methyl-4-nitrosopiperazine (MNP) is a nitrosamine impurity that has been found in certain medications, particularly rifampin, which is used to treat tuberculosis. Here are the key points about how MNP has affected human diseases and drug treatments:

Impact on Tuberculosis Treatment
Rifampin is a critical antibiotic used to treat tuberculosis (TB). The discovery of MNP contamination in rifampin products has raised concerns, but has not led to discontinuation of this important medication2.
The Centers for Disease Control and Prevention (CDC) recommends that providers continue prescribing rifampin for TB disease and latent TB infection treatment, as the risk of not taking the medicine outweighs any potential risk from nitrosamine exposure2.
Manufacturers are working to decrease MNP levels in rifampin products while the FDA has set temporary acceptable intake limits2.

Potential Cancer Risk
As a nitrosamine, MNP is considered a potential carcinogen, though its specific cancer risk in humans is not fully established2.
Nitrosamine impurities may increase cancer risk if people are exposed above acceptable intake levels over long periods2.
The acceptable intake limit approximates a 1:100,000 cancer risk over 70 years of daily dosing at that level2.

Impact on Drug Development and Studies
The presence of MNP in rifampin has affected clinical drug development:
Rifampin is commonly used as a strong CYP3A inducer in drug-drug interaction (DDI) studies4.
Reports of MNP contamination have hampered the conduct of clinical DDI studies using rifampin5.
Researchers are evaluating alternative CYP3A inducers for use in clinical studies to avoid potential issues related to MNP contamination4.

Regulatory Response
The discovery of MNP and other nitrosamines in medications has prompted regulatory action:
The FDA and other agencies have required manufacturers to review their products for potential nitrosamine contamination1.
Temporary acceptable intake limits have been set for MNP in rifampin (5 ppm) while efforts to reduce levels continue2.
Manufacturers must report to the FDA if MNP levels exceed the temporarily allowed limits2.
While the presence of MNP in rifampin has raised concerns, it has not directly affected the treatment of tuberculosis or other diseases for which rifampin is prescribed. However, it has impacted drug development processes and prompted increased scrutiny of medication manufacturing and quality control.

Affected Cellular Signaling Pathways
 

• ATM/ATR Signaling: DNA damage activates the ATM (Ataxia Telangiectasia Mutated) and ATR (ATM and Rad3-related) kinases, which initiate DNA damage response cascades2.
• p53 Pathway: The tumor suppressor p53 is often activated in response to DNA damage, leading to cell cycle arrest, DNA repair, or apoptosis if the damage is severe2.

• Checkpoint Activation: DNA damage checkpoints (G1/S, intra-S, and G2/M) may be activated, leading to cell cycle arrest to allow time for DNA repair2.
• Cyclin-Dependent Kinase Inhibition: Proteins like p21, which inhibit cyclin-dependent kinases, may be upregulated, further contributing to cell cycle arrest2.

• Intrinsic Apoptosis Pathway: Mitochondrial-mediated apoptosis may be activated, involving proteins like Bax and Bcl-22.
• Extrinsic Apoptosis Pathway: Death receptor-mediated apoptosis might also be triggered in response to cellular stress caused by MNP2.

• O6-Methylguanine-DNA Methyltransferase (MGMT): This enzyme directly repairs O6-methylguanine lesions, which are particularly mutagenic2.
• Base Excision Repair (BER): This pathway repairs other alkylated bases, such as N7-methylguanine and N3-methyladenine2.

• Nrf2 Pathway: The Nrf2 transcription factor may be activated, leading to the expression of antioxidant and detoxification genes3.
• Heat Shock Response: Cellular stress can trigger the heat shock response, leading to the expression of heat shock proteins (HSPs) that act as chaperones to protect cellular proteins3.