Image created in Bing

Genotoxic Chemicals in Pharmaceuticals: How to Identify

Table of Contents

• Introduction and Outcome
• Genotoxic chemicals and their chemical properties
• Genotoxic nature of Epoxides, Aromatic amines and Aromatic nitro compounds
  • Epoxides
  • Aromatic nitro compounds and Aromatic amines
• Factors affecting Genotoxicity
• Conclusion
• FAQ

Introduction and Outcome

Genotoxic chemicals or Genotoxic impurities damage genetic material in the cells through interactions with DNA sequence/ structure. Therefore, these chemicals are highly toxic. It is impossible to avoid these chemicals in pharmaceutical development and hence their control is required. But the biggest challenge is to identify and control these chemicals. In this post I will share skill based knowledge to identify these chemicals. After reading this post you will be able to predict genotoxic nature of any chemicals having seen the structure. I will also explain the genotoxic nature of several chemicals like epoxides, aromatic amines, and aromatic nitro compounds.

Genotoxic chemicals and their chemical properties

One of the most characteristics features of Genotoxic chemicals is that these chemicals electrophiles’ or converted into electrophiles the body. Electrophiles having the following characteristics:

1. They may be carbonium ions e.g. CH³⁺
2. They may be cations e.g. Cd²⁺, Al³⁺
3. They may be electron deficient molecules e.g. BF₃, AlCl₃
4. Molecules which may convert into cations in the body e.g. Epoxides, Aromatic compounds

Hence any chemicals with above catachrestic may be genotoxic in nature.

Genotoxic nature of Epoxides, Aromatic nitro compounds and Aromatic amines

Epoxides

Epoxides have a strained ring structure. This strained ring system of Epoxides facilitates the generation of a carbonium ion by opening the ring in the body (by the mechanism given below). This carbonium ion reacts with base pairs of DNA and damages the DNA. That is why Epoxides are Genotoxic.

(Structure drawn in ACD/ChemSketch)

Aromatic nitro compounds and Aromatic amines

The aromatic nitro compound is converted into Aromatic amino compound in the intestine by metabolic activation. This aromatic amine compound is oxidised to the N-hydroxy aryl amine. These aromatic amino compound and N-hydroxy aryl amine act electrophile (due to utilisation of amino group/-HN: lone pair of electrons in the ring by resonance). Hence, N-hydroxy aryl amine can react directly with DNA and can block replication of DNA. That is why Aromatic nitro compounds and Aromatic amines are genotoxic.

Factors affecting Genotoxicity

The following factors may affect the Genotoxic nature of Genotoxins

• Each positional isomer is equally Genotoxic
• Ortho Substation with positive inductive effect can enhance the Genotoxicity
• Ortho and meta substitution with bulky group can suppress the genotoxicity
• Bulky groups ortho to an aromatic amino or substituted amino or nitro groups abolish toxicity.
• Compounds with high molecular weight and big seize having very little chance to absorb
• Highly hydrophilic compounds are poorly absorbed and are easily excreted
• Compounds which are to reactive may not be carcinogenic because the hydrolyze or polarise before they can reach critical target in the cell.
• Planner molecules with electrophilic functional groups can intercalate properly ino DNA e.g. Polycyclic aromatic hydrocarbons, and Aflatoxin

Conclusion

Identifying the Genotoxic nature of any chemical is the challenging task for any profession. This approach is very helpful. Though this approach is not perfect but very useful in predicting the Genotoxic nature of untested molecules during drug development. I hope, this article has cleared all your doubts related to the structural identification of Genotoxic chemicals and enhanced your knowledge to the next level

References

• Genotoxic impurities; Strategies for identification and control-Andrew Teasdale

Abbreviations:

• GI: Genotoxic impurities
• DNA: Deoxyribonucleic acid

FAQs

What are the chemical properties of any Genotoxic chemical?

All Genotoxic chemicals are electrophiles like carbonium ions, cations and electron-deficient compounds

How Genotoxic chemicals/impurities can be predicted based on structure?

Based on structure genotoxic nature of any chemical can be predicted. All genotoxic chemicals are electrophiles or converted into electrophiles in the body

Why Epoxides, Aromatic amines and Aromatic nitro compounds are Genotoxins?

The aromatic nitro compound is converted into Aromatic amino compound in the intestine by metabolic activation. This aromatic amine compound is oxidised to the N-hydroxy aryl amine. These aromatic amino compound and N-hydroxy aryl amine act electrophile (due to utilisation of amino group/-HN: lone pair of electrons in the ring by resonance). Hence, N-hydroxy aryl amine can react directly with DNA and can block replication of DNA. That is why Aromatic nitro compounds and Aromatic amines are genotoxic.

What are the different factors affecting genotoxicity?

Several factors like substitution on the molecule, polarity of the molecule, size of the molecule, reactivity of the molecule and molecular weight affect the genotoxic nature of any chemicals

What are the Genotoxic material in the pharmaceutical industries?

Genotoxic materials are those chemicals which can damage the DNA like aromatic amino compounds, aromatic nitro compounds and epoxides

What is the example of genotoxic agent?

Genotoxic agents are those chemicals which can damage the DNA like aromatic amino compounds, aromatic nitro compounds and epoxides

What are Genotoxic and non-genotoxic chemicals?

Genotoxic chemicals damage the DNA whereas Non-genotoxic chemicals do not damage the DNA

What is the Genotoxic material?

Genotoxic materials are those chemicals which can damage the DNA like aromatic amino compounds, aromatic nitro compounds and epoxides