Selective Expression of CYP2A13 in Human Pancreatic α-Islet Cells

Abstract

ABSTRACT:Exposure to cigarette smoke is an etiological factor of human pancreatic cancer and has been associated with an increased risk of pancreatic diseases, including pancreatitis and diabetes. The toxicants in cigarette smoke can reach pancreatic tissue, and most of the toxicants require cytochrome P450 (P450)-mediated metabolic activation to exert their toxicity. Among all the human P450 enzymes, CYP2A13 is the most efficient enzyme in the metabolic activation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a major tobacco-specific toxicant and a suspected human carcinogen. It also metabolically activates 4-aminobiphenyl, another toxicant in cigarette smoke. Immunohistochemical analysis in this study demonstrated that CYP2A13 was selectively expressed in the islets but not in the exocrine portion of adult human pancreas. Further study using dual immunofluorescence labeling technique showed that CYP2A13 protein was mainly expressed in the ␣-islet but not in ␤-islet cells. The selective expression of CYP2A13 in human pancreatic ␣-islet cells suggests that these islet cells could be damaged by the toxicants existing in cigarette smoke through CYP2A13-mediated in situ metabolic activation. Our result provides a mechanistic insight for human pancreatic diseases that have been associated with cigarette smoke exposure.

Genetic and Enzymatic Characteristics of CYP2A13 in Relation to Lung Damage

“…Unexpectedly, CYP2A13 was found to be expressed in pancreatic α-islet cells by using immunohistochemical analysis (IHC) [16]. Additionally, this enzyme was not expressed in the exocrine portion of the adult human pancreas, nor β-islets.…”

Structural Impact Assessment of Cytochrome P450 2A13 Polymorphisms Using Molecular Dynamics Simulations

“…Immunohistochemical analysis revealed the expression of CYP2A13 in pancreatic alpha islet cells, suggesting its involvement as a molecular factor contributing to the significantly higher risk of pancreatic cancer in current smokers. 5,6) Furthermore, CYP2A13 has been reported to be expressed in various other tissues, including the liver, testis, breasts, uterus, ovary, and coronary endothelial cells, with a notable presence in the bladder. 7,8) CYP2A13 comprises 494 amino acid residues and shares a 93.5% similarity with CYP2A6.…”