Inhibition of Carcinogen-Activating Cytochrome P450 Enzymes by Xenobiotic Chemicals in Relation to Antimutagenicity and Anticarcinogenicity

Abstract

A variety of xenobiotic chemicals, such as polycyclic aromatic hydrocarbons (PAHs), aryl-and heterocyclic amines and tobacco related nitrosamines, are ubiquitous environmental carcinogens and are required to be activated to chemically reactive metabolites by xenobiotic-metabolizing enzymes, including cytochrome P450 (P450 or CYP), in order to initiate cell transformation. Of various human P450 enzymes determined to date, CYP1A1, 1A2, 1B1, 2A13, 2A6, 2E1, and 3A4 are reported to play critical roles in the bioactivation of these carcinogenic chemicals. In vivo studies have shown that disruption of Cyp1b1 and Cyp2a5 genes in mice resulted in suppression of tumor formation caused by 7,12-dimethylbenz[a]anthracene and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, respectively. In addition, specific inhibitors for CYP1 and 2A enzymes are able to suppress tumor formation caused by several carcinogens in experimental animals in vivo, when these inhibitors are applied before or just after the administration of carcinogens. In this review, we describe recent progress, including our own studies done during past decade, on the nature of inhibitors of human CYP1 and CYP2A enzymes that have been shown to activate carcinogenic PAHs and tobacco-related nitrosamines, respectively, in humans. The inhibitors considered here include a variety of carcinogenic and/or non-carcinogenic PAHs and acethylenic PAHs, many flavonoid derivatives, derivatives of naphthalene, phenanthrene, biphenyl, and pyrene and chemopreventive organoselenium compounds, such as benzyl selenocyanate and benzyl selenocyanate; o-XSC, 1,2-, 1,3-, and 1,4-phenylenebis(methylene)selenocyanate.

Effect of a Benign Prostatic Hyperplasia (BPH) Xenobiotic - Croton membranaceus Müll.Arg. Root Extract on CYP1A2, CYP3A4, CYP2D6, and GSTM1 Drug Metabolizing Enzymes in Rat Model

“…CYP1A2 was the only phase 1 DME that showed a different trend by increasing. CYP1A2 metabolizes various environmental procarcinogens, such as heterocyclic amines, nitrosamines, and a atoxin B 1 [28].…”

“…CYP1A2 is important for the metabolism of endogenous substrates [36] and activation of many environmental carcinogens including dietary heterocyclic amines, certain mycotoxins, tobacco-speci c nitrosamines, and aryl amines [28]. It has been suggested that sustained induction of CYP1A2 for example, maybe bene cial in women, as through 2-hydroxylation it increases estrogen clearance to antioestrogenic metabolites, so acting to protect against estrogen-driven tumors [37].…”

MicroRNAs and cancer drug resistance: over two thousand characters in search of a role

“…CYP1B1 is highly expressed in oestrogen target tissues and catalyses the metabolic activation of several procarcinogens (e.g., heterocyclic amines, polycyclic hydrocarbons) and the 4-hydroxylation of 17β-oestradiol [27,28] . It is also abundant in tumour tissues.…”

Molecular Insights on the Interactions of Nitrosamines from Cigarette Smoking with CYP2A13 using Molecular Docking and Molecular Dynamics Simulation

“…The molecules present in tobacco and tobacco smoke begin to act in the body only after enzymatic activation that can be achieved by cytochrome P450 2A13 (P450 or CYP) and is considered a key reaction pathway for initiation of bioactivation of carcinogenesis, and consequently of the progressive changes in the biological profile of the cell [13,14].…”