Toxicological studies with dithranol and its 10-acyl analogues

Area of Science:

• Toxicology
• Pharmacology
• Genetics

Background:

• Dithranol is an antipsoriatic drug.
• 10-acyl analogues of dithranol were synthesized to evaluate their toxicological profiles.
• Understanding the mutagenicity of these compounds is crucial for drug safety assessment.

Purpose of the Study:

• To assess the oral toxicity (LD50) of dithranol and its 10-acyl analogues in mice and rats.
• To evaluate the in vitro mutagenic potential of these compounds using bacterial assays (Salmonella typhimurium, Escherichia coli) and human lymphocyte cultures.
• To determine the in vivo genotoxic effects using the mouse micronucleus test.

Main Methods:

• Oral LD50 determination in NMRI mice and Wistar rats.
• Bacterial mutagenicity assays (Ames test) with Salmonella typhimurium and Escherichia coli.
• In vitro cytogenetic analysis of human lymphocytes.
• In vivo mouse micronucleus test.

Main Results:

• Dithranol analogues, including butantrone, were more toxic than dithranol in rodents.
• Compounds showed mutagenicity in Salmonella typhimurium TA1537 but not in other bacterial strains.
• Butantrone displayed the lowest bacterial toxicity and mutagenicity.
• In vitro, dithranol and some analogues induced chromosome gaps in human lymphocytes, but butantrone did not.
• No in vivo clastogenic activity was observed for dithranol or butantrone in the mouse micronucleus test.

Conclusions:

• Dithranol and its 10-acyl analogues possess weak in vitro mutagenic activity.
• Butantrone demonstrates a lower mutagenic potential compared to dithranol and other analogues.
• The compounds lack significant in vivo genotoxicity at maximum tolerated doses.