2.8:
Mutagenicity and Carcinogenicity
Drug-induced modification of DNA is called mutagenicity. If the mutations affect the tumor suppressor genes or proto-oncogenes, it can lead to carcinogenesis.
Carcinogenesis begins with tumor initiation. Here, a genotoxic carcinogen—called an initiator—mutates a gene to inhibit cellular apoptosis and promote proliferation.
This is followed by the tumor promotion step, where an epigenetic carcinogen —called a promoter—alters the cellular environment to promote the survival of pre-cancerous cells.
The IARC categorizes chemicals into four groups based on their carcinogenic potential.
The genotoxic potential of such carcinogens is assessed using in vitro and in vivo tests.
In vitro mutagenicity tests such as the Ames test, chromosome aberrations and sister chromatid exchange assays are rapid and inexpensive, but they can have some false results.
In vivo carcinogenicity tests involve chronic dosing in animals, followed by the detection of tumors. Although expensive and time-consuming, they are required to assess the risks to human health.
2.8:
Mutagenicity and Carcinogenicity
Mutagenicity and carcinogenicity refer to the ability of drugs to cause genetic defects and induce cancer, respectively. The International Agency for Research on Cancer (IARC) classifies agents into four groups based on their carcinogenic potential. Group 1 agents are known human carcinogens; group 2A agents are probably carcinogenic to humans; group 3 agents lack data to support their role in carcinogenesis; and group 4 includes agents for which data support that they are not likely to be carcinogens.
Reactive metabolites formed during drug oxidation can lead to structural abnormalities in chromosomes and mutations in DNA. Some mutations can result in the development of cancer by affecting genes that regulate cell growth. Carcinogenesis can also occur through non-DNA interactions, where chemicals modify signaling pathways and the cellular environment to promote the survival and proliferation of pre-cancerous cells.
Assessing mutagenicity and carcinogenicity involves in vitro and in vivo assays. In vitro tests, including the Ames test, mouse lymphoma cell assay, and chromosome aberration assay, help screen compounds but have limited predictive value for carcinogenicity. Regulatory authorities require time-consuming and expensive whole animal in vivo tests before licensing drugs for clinical use. Substances with mutagenic and carcinogenic potential include anticancer drugs, estrogens, tobacco, and radioisotopes.