Weak CYP1A Inducers: A Potential Role in Prevention and Therapy of Chemcially-Induced Cancer
Institute of Molecular Biology and Biophysics SB RAMS, Novosibirsk, Russia
Series: Cancer Etiology, Diagnosis and Treatments
Cytochromes P450 1A sub-family (CYP1A1 and CYP1A2) are well-known metabolizers of anthropogenic compounds such as polycyclic aromatic hydrocarbons (PAHs) and arylamines. They catalyze all metabolic reactions occurring with PAHs in the organism including the ones resulting in the formation of carcinogenic, mutagenic and teratogenic substances. PAH in their intact, exogenous form usually do not produce adverse effects on the organism (except rare cases of acute poisoning with extremely high doses), however, their metabolites are able to bind and damage macromolecules in the cells. PAHs characterized by specific physical and chemical properties: they are hydrophobic, planar molecules with the size of approximately 6.8 x 13.7 Ã…. In organisms, PAH activate expression of CYP1A and serve as their substrates. PAH-like inducers of CYP1A are called “classic” inducers. They increase CYP1A activity hundreds fold, undergo metabolic activation and, afterwards, become able to promote the development of dangerous diseases including chemically-induced cancer.
Recent studies demonstrate an increasing number of non-PAH-like CYP1A inducers, which have different physical and chemical properties. These substances include endogenous compounds and food components, such as indoles, flavonoids, vitamins, and some others. They are so-called “weak” or “non-classical” CYP1A inducers and they increase the enzyme activity not more than several times. This mild activation of CYP1A by naturally-occuring substances probably has a physiological function and is not dangerous for organisms.
At least some â€œweakâ€ CYP1A inducers are able to inhibit the effect of “classic” inducers such as 2,3,7,8-Tetrachlorodibenzodioxin (TCDD) or benzo(α)pyrene in the case of combined administration. Since classic inducers are metabolized by CYP1A to reactive intermediates able to cause chemically-induced cancer and other diseases, the suppression of CYP1A activity might be a useful tool for their prevention and/or management. Thus, detailed understanding of molecular mechanisms underlying this phenomenon is required. Further investigation of â€œweakâ€ CYP1A inducers might result in the development of new medical strategies to prevent or fight adverse effects of PAH-like anthropogenic xenobiotics. (Imprint: Nova)
Table of Contents
AHR STRUCTURE, FUNCTION AND SIGNALING. MECHANISM OF CYP1A INDUCTION
OVERVIEW OF WEAK CYP1A INDUCERS
MECHANISMS OF INHIBITION OF AHR ACTIVATION AND CYP1A INDUCTION
THE INHIBITION OF PAH-INDUCED CYP1A1 ACTIVATION
THE INHIBITION OF PAH-INDUCED CYP1A1 BY WEAK AHR LIGANDS / CYP1A INDUCERS