Abstract
Cytochrome P450 (CYP) epoxygenases, a multi-gene superfamily of heme-containing enzymes, are commonly known to metabolize endogenous arachidonic acid (AA) to epoxyeicosatrienoic acids (EETs). The role of CYPs is mostly studied in liver drugs metabolism, cardiac pathophysiology, and hypertension fields. Particularly, the biological functions of these enzymes have increasingly attracted a growing interest in cancer biology. Most published studies on CYPs in cancer have been limited to their role as drug metabolizing systems. The activity of these enzymes may affect drug pharmacokinetics and bioavailability as well as exogenous compounds turnover. Some CYP isoforms are selectively highly expressed in tumors, suggesting a potential mechanistic role in promoting resistance to chemotherapy. Majority of drugs elicit their effects in extrahepatic tissues whereby their metabolism can significantly determine treatment outcome. Nonetheless, the role of extrahepatic CYPs is not fully understood and targeting these enzymes as effective anti-cancer therapies are yet to be developed. This review article summarizes an up-to-date body of information from published studies on CYP enzymes expression levels and pathophysiological functions in human normal and malignant gastrointestinal (GI) tract tissues. Specifically, we reviewed and discussed the current research initiatives by emphasizing on the clinical significance and the pathological implication of CYPs in GI malignancies of esophagus, stomach, and colon.
Highlights
The increasing incidence of gastrointestinal (GI) malignancies may be linked to a Westernization of lifestyle and risk behavior [1,2,3]
The role of Cytochrome P450 (CYP) is mostly studied in liver drugs metabolism, cardiac pathophysiology, and hypertension fields
Endogenous arachidonic acid (AA) as a substrate [11] is converted by CYP ω-hydroxylases to hydroxyeicosatetraenoic acids (HETEs) and by CYP epoxygenases to 5,6, 8,9, 11,12, and 14,15 epoxyeicosatrienoic acids (EETs) [12]
Summary
The increasing incidence of gastrointestinal (GI) malignancies may be linked to a Westernization of lifestyle and risk behavior [1,2,3]. The analysis of CYP1A, CYP2A, CYP2E1, CYP3A, and CYP4A protein levels in 25 nonneoplastic surgical tissue specimens of human esophageal mucosa did not reveal any significant associations with the patients’ medical history data and known esophageal cancer risk factors, such as tobacco smoke and GERD [24] These unexpected results were explained by the small number of studied samples that impeded the authors from making any conclusions regarding the connection between CYPs expression and esophageal cancer. The activities of xenobiotic-metabolizing enzymes were decreased by 30–50% in the squamous cell carcinomas as compared to their corresponding non-cancerous mucosa [66] Another potent esophageal carcinogen, N-methyl-N-pentylnitrosamine, was metabolized by CYPs in microsomal fractions of human and rat esophagus [68]. Barrett’s esophagus/esophageal squamous CYP1A2, CYP3A4, CYP2E1, CYP2C9/10 mucosa
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