Effect of starvation and chlormethiazole on cytochrome P450s of rat nasal mucosa

Cytochrome P450 (CYP) enzymes of nasal tissue are relatively resistant to i nduction by classical inducers. In the present study, the effects of starva tion on the expression of CYP1A, 2A, 2B, 2C, 2E, 2G, and 3A subfamilies in the nasal mucosa of rat were studied. Fasting for 72 hr caused an increase in 2E1-dependent p-nitrophenol hydroxylase and 1A-dependent ethoxy- (or met hoxy) resorufin dealkylase activities, but did not affect either 2A-linked coumarin hydroxylase or the testosterone hydroxylase activity, the latter r eaction being a marker of several CYPs including 2G1. Whereas increases in 2E1- and 1A- associated catalytic activities were accompanied by a concomit ant increase in the corresponding apoproteins as determined by immunoblotti ng, immunoactive protein bands reactive with antibodies raised against rat 1A1, 2B1, 2C11, 3A1 or rabbit nasal 2A10/11 and 2G1 were not altered. Fasti ng also increased CYP2E1 and CYP1A2 on the mRNA level, but did not alter CY P1A1 mRNA as determined by hybridization with cDNA probes selective for the se cytochromes. A reiterative administration of chlormethiazole, a specific inhibitor of 2E1 in liver, strongly inhibited many CYPs, including 2E1, 1A 2, 2G1, and 2A in the nasal mucosa, but did not influence expression of 2B or 3A as determined by immunoblotting or catalytic activities. The chlormet hiazole mediated inhibition of 1A1 and 2E1 was demonstrated to be at the mR NA level. These results suggest that fasting induces the gene expression of 2E1 and 1A2 and that the mechanisms involved in the regulation of CYPs in the nasal mucosa are tissue specific. The inducibility of the above-mention ed isoforms may have a significant role in the clearance of drugs and bioac tivation of inhaled compounds. BIOCHEM PHARMACOL 59;11:1425-1432, 2000. (C) 2000 Elsevier Science Inc.