Toxicity generating mechanisms

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This post assumes you are well-versed with electrophiles and nucleophiles along with basics of Biology. If not, here are some links for you that can help.

Electrophilic substitution or those metabolized to electrophilic species are capable of reacting covalently with nucleophilic substituents of cellular macromolecules such as DNA, RNA, enzymes, proteins and others.

Nucleophilic toxic substituents

  • Thiol groups of cysteinyl residue in protein
  • S atoms of methionyl residue in protein
  • Primary amino groups of argimine and lysine residues
  • Secondary groups (histidine) in protein
  • Amino groups of purine bases in DNA or RNA
  • O atoms of purines and pyrimidines
  • P=O of RNA and DNA

These are the groups highly likely to cause such effects but the effects can be reduced or eliminated by replacing the functional group or by changing its position in the molecule. Hence, the presence of any of these substituents does not automatically mean that the substance is or will be toxic.

Let’s look at some examples.

Example 1

Ethyl Acrylate (Carcinogenic)

Acrylates contain alpha, beta unsaturated C=O system and undergo Michael addition. This is the reason for carcinogenic properties of acrylates. Methacrylates are better than acrylates. Incorporation of a CH3 group on to the alpha C to give ethacrylates decreases the electrophilicity (i.e. reactivity) of the beta C. Hence, methacrylates do not undergo 1,4-michael addition easily. Methacrylates have some commercial efficacy.

Example 2

Isocyanates are used in adhesives and intermediates. The endogeneous nucleophiles in isocyanates are responsible for their toxicity. During coating, the ketoxime moiety is removed thermally thereby regenerating the isocyanate.

Example 3

Vinyl sulfolane are:

  • highly electrophilic
  • used in textile fibre industry
  • reacts covalently with hydroxy groups of cellulose fibres
  • is made safe by converting into a sulfate ester which is not electrophilic during storage and handling. It can be regenerated again by neutralizing.

Example 4

Structural requirements for high teratogenic potency of carboxylic acids? *

IMG-1463 (1).jpg

What aspects of this molecule can lead to teratogenic potency?

  • a free carbonyl group
  • only one hydrogen atom at C(2)
  • an alkyl substituent larger than methyl at C(2)
  • no double bonds between C(2) and C(3) or C(3) and C(4)

*Teratogenic potency is based on in vivo data.

To summarize:

  • Ortho or meta substituents are better.
  • Reduce alkyl chain carbons.
  • Methyl is better than ethyl.
This article was last edited on December 19th, 2017 for accuracy.

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