Hypothesis: chemical carcinogenesis mediated by a transiently active carcinogen receptor

Abstract

Biologically active small-molecular-weight compounds are actively transported into the cell nucleus by a specific receptor. This has been widely demonstrated for retinoids, polycyclic hydrocarbons (such as steroids), and dioxin. Thus, it is reasonable to assume that genotoxically active polycyclic hydrocarbons, and possibly all genotoxically active small-molecular-weight substances, exert their transformational effect in the cell nucleus via a specific receptor. I propose that the receptor is activated only at the end of the G₁ phase of the cell cycle and that the carcinogen receptor complex interferes directly with DNA synthesis, leading to mutations. This hypothesis may account for various characteristics of malignant growth, such as the organ specificity of carcinogens and the relationship between cell proliferation and malignant transformation. If so, it could form the basis for establishing a radioreceptor assay for carcinogens.

Chemical carcinogenesis

“…DNA damage can be repaired by enzymatic mechanisms (Bertram 2001, Jeng et al 2001, Shacter and Weitzman 2002. Cells which are proliferating have less time to repair the damaged DNA and remove co- valent bonds that chemicals establish with the DNAknown as adducts (Heidelberger 1977, Richardson et al 1986, Frowein 2000.…”

“…In high doses, they cause toxicity and cell proliferation, increasing DNA replication and influencing its carcinogenic activity (Cohen 1998). Following transmembranar diffusion they are metabolized in electrophilic compounds that enter the nucleus and interact with nucleophilic sites (DNA, RNA and proteins) changing their structural integrity and establishing covalent bonds known as adducts (Miller and Miller 1975, Straub and Burlingame 1981, Cohen et al 1992, Ashby 1996, Weisburger 1998, Frowein 2000, Bertram 2001, Lutz 2001, Williams 2001, Baird and Mahadevan 2004. The formation of adducts constitutes the first critical step of carcinogenesis and if these are not repaired before DNA replication then mutations may occur in the proto-oncogenes and tumour suppressor genes, which are essential for the initiation stage (Sobels 1975, Barrett and Wiseman 1987, Farmer 1994, Lutz 2001, Williams 2001, Li et al 2005.…”