Role of the modulation of CYP1A1 expression and activity in chemoprevention

Abstract

As one of the main extra-hepatic cytochrome P450 (CYP) enzymes, CYP1A1 has been comprehensively investigated for its ability to metabolize both exogenous and endogenous compounds into their carcinogenic derivatives. These derivatives are linked to cancer initiation and progression. The compound benzo-a-pyrene (BaP), a copious and noxious compound present in coal tar, automobile exhaust fumes, cigarette smoke and charbroiled food, is metabolised by CYP1A1 and has been studied in great detail. Other compounds reliant on the same enzyme for their activation include 7,12 dimethylbenz(a)anthracene (DMBA) and heterocyclic amine, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). This review takes an in-depth look at a number of phytochemicals, plant extracts and a few synthetic compounds that have been researched and deemed potential chemopreventives via their interaction with the activity and expression of CYP1A1. It will also review a useful active site model of CYP1A1. Based on inhibitors of CYP1A1 that have demonstrated in vivo use as chemopreventors, CYP1A1 is a useful initial target for screening compounds with such potential, with the use of rapid in vitro and/or in silico assessments. Chemoprevention is a means by which healthy tissues are protected via the prevention, inhibition or reversal of carcinogenesis. This review focuses on one important pathway of carcinogenesis and identifies the important role that CYP1A1 plays in that pathway. It is hoped that highlighting the importance of such a key target, will help revive further research into and application of inhibitors of CYP1A1 towards generating improved chemopreventors.

Inhibitory effect of synthetic cannabinoids on CYP1A activity in mouse liver microsomes

“…The changes in the enzymatic activity of P450 frequently cause drug-drug interactions. CYP1A is a subfamily of P450 involved in the metabolism of clinical drugs and environmental pollutants, such as acetaminophen, caffeine, and benzo(a)pyrene (Zhou et al, 2009;Badal and Delgoda, 2014). Cannabinol (CBN) and cannabidiol (CBD), the major cannabinoids present in marijuana, strongly inhibit the enzymatic activity of CYP1A isoforms (Yamaori et al, 2010).…”

Mate Intake and Risk of Breast Cancer in Uruguay: a Case-Control Study

“…DMBA is an important environmental contaminant that collaborates in generating several oxidative stress-mediated diseases, including cancer, but it has another relevant feature: it is a fat-soluble compound and because of this property it accumulates and persists in the adipose tissue of the mammary gland, therefore increasing the exposure of mammary epithelium to this chemical carcinogen (Ayyakkannu et al, 2014). Interestingly, DMBA, like BaP, is also an indirect-acting carcinogen, requiring metabolic activation to yield its ultimate carcinogenic form (Badal and Delgada, 2014), in particular an oxidation by CYP enzymes (Szaefer et al, 2014). Unlike the hot temperature of the infusion -accepted as a risk factor for cancers of the upper aerodigestive tract (De Stefani et al, 1988;1990;Lubin et al, 2014)-, the quoted components could be partially responsible of the association of 'mate' with cancer in organs which have no direct contact with the beverage: lung (De Stefani et al, 1996), bladder (De Stefani et al, 1991;2007), kidney (De Stefani et al, 1998b), prostate (De Stefani et al, 2011b) and also cervix uteri (De Stefani et al, 2011a).…”

Activation of aryl hydrocarbon receptor reduces carbendazim-induced cell death

“…In contrast, the monooxygenase activity of CYP1A1 introduces an epoxide to BaP, and in turn, epoxide hydrolase hydrolyzes the epoxide to produce diol derivatives, e.g. B[a]P-7,8-diol (Badal and Delgoda, 2014;Shimada, 2006). B[a]P-7,8-diol may be further converted to B[a]P diol epoxide (BPDE).…”

“…B[a]P-7,8-diol may be further converted to B[a]P diol epoxide (BPDE). BDBP has been shown to bind to DNA and is regarded as a carcinogenic derivative (Badal and Delgoda, 2014;Zhang et al, 2012). BDBP may also interact with other cellular components, resulting in cell death or damage.…”