Olfactory cytochrome P-450. Studies with suicide substrates of the haemoprotein.
1. The olfactory epithelium of male hamsters has been found to be extremely active in the cumene hydroperoxide-supported oxidation of tetramethylphenylenediamine, and this peroxidase activity has been shown to be cytochrome P-450-dependent. 2. The interaction of a series of suicide substrates of cytochrome P-450 with the hepatic and olfactory mono-oxygenase systems has been assessed by determination of peroxidase, 7-ethoxycoumarin O-de-ethylase (ECOD) and 7-ethoxyresorufin O-de-ethylase (EROD) activities after treatment in vivo with these compounds. Chloramphenicol, OOS-trimethylphosphorothiolate and two dihydropyridines [DDC (3,5-diethoxycarbonyl-1,4-dihydrocollidine) and 4-ethyl DDC (3,5-diethoxycarbonyl-4-ethyl-1,4-dihydro-2,6-dimethylpyridine)] all caused similar percentage inhibitions of hepatic and olfactory activities, but the absolute amounts of enzymic activity lost were considerably greater in the latter tissue. In contrast, halothane had little effect upon hepatic cytochrome P-450-dependent reactions, whereas it severely inhibited those of the olfactory epithelium. 3. The time course of loss and recovery of hepatic and olfactory peroxidase, ECOD and EROD activities after a single dose of 4-ethyl DDC was studied. The rates of loss of activity observed were very similar, irrespective of tissue or reaction examined. In the olfactory epithelium, all three activities recovered concurrently and at a rate similar to that of the hepatic peroxidase activity. In contrast, the hepatic de-ethylation of 7-ethoxycoumarin and 7-ethoxy-resorufin recovered significantly more rapidly. 4. It is suggested that this behaviour is due to 4-ethyl DDC acting not only as a suicidal inhibitor but also as an inducer of certain forms of cytochrome P-450 in the liver; in the olfactory epithelium, however, inactivation, but not induction, occurs. Classical inducing agents were reported to have no effect upon olfactory cytochrome P-450, and in the present study neither phenobarbitone nor beta-naphthoflavone treatment had any effect upon olfactory cytochrome P-450-dependent reactions, although it induced those of the liver.
Reed
C J
CJ
MRC Toxicology Unit, MRC Laboratories, Carshalton, Surrey, U.K.
Lock
E A
EA
De Matteis
F
F
D015660:7-Alkoxycoumarin O-Dealkylase; D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D006224:Cricetinae; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003997:Dicarbethoxydihydrocollidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004848:Epithelium / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008647:Mesocricetus; D009245:NADH Dehydrogenase / Q000378:metabolism; D009831:Olfactory Mucosa / Q000187:drug effects / Q000201:enzymology*; D010088:Oxidoreductases / Q000378:metabolism; D010105:Oxygenases / Q000378:metabolism; D010544:Peroxidases / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D019324:beta-Naphthoflavone
D001571:Benzoflavones; C030826:3,5-dicarbethoxy-2,6-dimethyl-4-ethyl-1,4-dihydropyridine; D019324:beta-Naphthoflavone; D003997:Dicarbethoxydihydrocollidine; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D010544:Peroxidases; D010105:Oxygenases; D015660:7-Alkoxycoumarin O-Dealkylase; D019363:Cytochrome P-450 CYP1A1; D009245:NADH Dehydrogenase; D010634:Phenobarbital