Received for publication February 9, 2005.
Revised May 4, 2005.
Accepted for publication May 4, 2005.

Characterization of microsomal CYP-dependent monooxygenases in the rat olfactory mucosa

Abstract

Nasal administration of a drug ensures therapeutic action by rapid systemic absorption and/or the entry of some molecules into the brain through different routes. Many recent studies have pointed out the presence of xenobiotic metabolizing enzymes in rat olfactory mucosa (OM). Nevertheless, very little is known about the precise identity of isoforms of CYP-dependent monooxygenases (CYP) and their metabolic function in this tissue. Therefore, we evaluated mRNA expression of 19 CYP isoforms by semi-quantitative RT-PCR and measured their microsomal activity toward six model substrates. For purposes of comparison, studies were conducted on OM and the liver. Specific activities toward phenacetin, chlorzoxazone and dextrometorphan are higher in OM than in the liver; those toward lauric acid and testosterone are similar in both tissues and that toward tolbutamide is much lower in OM. There are considerable differences between the two tissues with regard to mRNA expression of CYP isoforms. Some isoforms are expressed in OM but not in the liver (CYP1A1, 2G1, 2B21 and 4B1), whereas mRNA of others (CYP2C6, 2C11, 2D2, 3A1, 3A2 and 4A1) are present only in hepatic tissue. Although expression of CYP1A2, 2A1, 2A3, 2B2, 2D1, 2D4, 2E1, 2J4 and 3A9 is noticed in both tissues, there are a number of quantitative differences. On the whole, our results strongly suggest that CYP1A1, 1A2, 2A3, 2E1, 2G1 and 3A9 are among the main functional isoforms present in OM, at least regarding activities toward the 6 tested substrates. The implication of olfactory CYP-dependent monooxygenases in toxicology, pharmacology and physiology should be further investigated.

Key words: CYP expression, cytochrome P450, extrahepatic cytochrome P450, extrahepatic drug metabolism