Cell-specific Expression of CYP2A5 in the Mouse Respiratory Tract: Effects of Olfactory Toxicants

Abstract

We performed a detailed analysis of mouse cytochrome P450 2A5 (CYP2A5) expression by in situ hybridization (ISH) and immunohistochemistry (IHC) in the respiratory tissues of mice. The CYP2A5 mRNA and the corresponding protein co-localized at most sites and were predominantly detected in the olfactory region, with an expression in sustentacular cells, Bowman's gland, and duct cells. In the respiratory and transitional epithelium there was no or only weak expression. The nasolacrimal duct and the excretory ducts of nasal and salivary glands displayed expression, whereas no expression occurred in the acini. There was decreasing expression along the epithelial linings of the trachea and lower respiratory tract, whereas no expression occurred in the alveoli. The hepatic CYP2A5 inducers pyrazole and phenobarbital neither changed the CYP2A5 expression pattern nor damaged the olfactory mucosa. In contrast, the olfactory toxicants dichlobenil and methimazole induced characteristic changes. The damaged Bowman's glands displayed no expression, whereas the damaged epithelium expressed the enzyme. The CYP2A5 expression pattern is in accordance with previously reported localization of protein and DNA adducts and the toxicity of some CYP2A5 substrates. This suggests that CYP2A5 is an important determinant for the susceptibility of the nasal and respiratory epithelia to protoxicants and procarcinogens.

CYP2A13 in Human Respiratory Tissues and Lung Cancers: An Immunohistochemical Study with A New Peptide-Specific Antibody

“…The cellular localization pattern of CYP2A13 protein in human respiratory tract is much more similar to that of CYP2S1. It is also very similar to the expression of CYP2A5 protein in mouse respiratory tract (Piras et al, 2003), although mouse CYP2A5 but not CYP2A13 is mainly expressed in the liver (Ulvila et al, 2004). The tissue-and cell-specific expression of human P450 enzymes is believed to play a critical role in the metabolism in situ of various P450 substrates, including the metabolic activation of chem- ical carcinogens in the target tissues/cells.…”

Cytochrome P450 2A5 and bilirubin: Mechanisms of gene regulation and cytoprotection

“…Cytochrome P450 2A5 (CYP2A5) is a murine orthologue of the human nicotinemetabolizing enzyme CYP2A6 and is located primarily in the endoplasmic reticulum (ER) of the liver and olfactory mucosa of mice (Juvonen et al, 1985;Su et al, 1996;Piras et al, 2003;Sangar et al, 2010). CYP2A5 can be also found in mitochondrial membranes and the recent study suggests that mitochondrial CYP2A5 may play a role in the oxidative stress response (Honkakoski et al, 1988;Genter et al, 2006).…”

“…CYP2A5 is primarily located in the endoplasmic reticulum and mitochondrial membranes of the liver and olfactory mucosa of mice Su et al, 1996;Piras et al, 2003;Genter et al, 2006;Sangar et al, 2010). CYP2A5 is an interesting enzyme for its unique regulation and its involvement in liver injury caused by various well-known pathological conditions or hepatotoxins.…”

Cyp2a5-Mediated Activation and Early Ultrastructural Changes in the Olfactory Mucosa: Studies on 2,6-Dichlorophenyl Methylsulfone

“…We propose that lesions induced by 2,6-diClPh-MeSO 2 in the mouse olfactory mucosa were initiated by a P450-mediated bioactivation in the Bowman's glands and depletion of NP-SH levels, leading to disruption of ion homeostasis, organelle swelling, and cell death. The high expression of CYP2A5 in the olfactory mucosa is suggested to play a key role for the tissue-specific toxicity induced by 2,6-diClPh-MeSO 2 .The olfactory mucosa harbors a wide variety of xenobiotic-metabolizing enzymes including several cytochrome P450 (P450) forms; the most predominant are CYP2A3/5/10/13 and CYP2G1 (Ding and Kaminsky, 2003;Piras et al, 2003;Ling et al, 2004). The P450-mediated metabolism is generally regarded as a protection mechanism, and the high expression of drug-metabolizing P450s is most likely related to the clearance of odorants and other airborne chemicals.…”