Related Experiment Videos
Modulation of rat guanylate cyclase activity in vitro by chemical carcinogens
Abstract:
The nucleotide cyclic GMP has been reported to be involved in cell proliferation and malignant transformation. Nitroso chemical carcinogens activate the enzyme guanylate cyclase (EC 4.6.1.2) which catalyzes the production of cyclic GMP. The present investigation demonstrates that compounds from other major classes of carcinogens including (1) alpha-halo ethers (chloromethyl methyl ether); (2) aromatic amines (benzidine and B-naphthylamine); (3) polycyclic hydrocarbons (1,2-benzanthracene and acridine); (4) azo dyes (p-dimethylaminoazobenzene), and (5) aflatoxins (B1, B2, G1, G2) produced a striking and significant inhibition of guanylate cyclase over a general concentration range of 0.5-13 mmol/1 in a variety of tissues. Some of the nitrosamides which increase guanylate cyclase activity, increase DNA synthesis whereas carcinogens which decrease guanylate cyclase activity inhibit DNA or RNA synthesis suggesting a relationship between cyclic GMP, DNA synthesis, and chemical carcinogenesis.
Insights
Chemical carcinogens inhibit guanylate cyclase, an enzyme crucial for cyclic GMP production. This inhibition of cyclic GMP synthesis correlates with reduced DNA and RNA synthesis, suggesting a link to chemical carcinogenesis.
Area of Science:
- Biochemistry
- Molecular Biology
- Toxicology
Background:
- Cyclic guanosine monophosphate (cGMP) plays a role in cell proliferation and malignant transformation.
- Guanylate cyclase (EC 4.6.1.2) catalyzes cGMP production and is activated by nitroso chemical carcinogens.
Purpose of the Study:
- To investigate the effect of various chemical carcinogen classes on guanylate cyclase activity.
- To explore the relationship between guanylate cyclase activity, DNA synthesis, and chemical carcinogenesis.
Main Methods:
- In vitro assessment of guanylate cyclase activity.
- Exposure of various tissues to different classes of chemical carcinogens.
- Measurement of DNA and RNA synthesis.
Main Results:
- Major classes of carcinogens, including alpha-halo ethers, aromatic amines, polycyclic hydrocarbons, azo dyes, and aflatoxins, significantly inhibited guanylate cyclase activity.
- The inhibition occurred over a concentration range of 0.5-13 mmol/1 in various tissues.
- Carcinogens that decreased guanylate cyclase activity also inhibited DNA or RNA synthesis.
Conclusions:
- Chemical carcinogens, beyond nitroso compounds, can inhibit guanylate cyclase.
- A potential link exists between cyclic GMP metabolism, DNA/RNA synthesis inhibition, and the mechanism of chemical carcinogenesis.