The in vitro effects of alkanes, alcohols, and ketones on rat lung cytochrome P450-dependent alkoxyphenoxazone dealkylase activities.
The sensitivities of cytochrome P450 (EC 1.14.14.1)-dependent benzyloxy- and ethoxyphenoxazone dealkylase (BzOPh'ase and EtOPh'ase, respectively) activities towards a series of aliphatic hydrocarbons were measured in the microsomal fraction of lung obtained from beta-naphthoflavone-treated rats. The unsubstituted hydrocarbons were straight-chain (n-hexane through n-undecane) and branch-chain (eight carbons). The substituted compounds were alcohols and ketones of hexane and octane. The data are expressed as I50 values, i.e. the hydrocarbon concentration required to cause 50% decrease in the rate of enzyme-catalyzed product (resorufin) formation. The unsubstituted aliphatic hydrocarbons exhibited I50 values towards BzOPh'ase from 0.76 microM (2,5-dimethylhexane) to 8.8 microM (n-hexane). The lung EtOPh'ase activity was insensitive towards the tested unsubstituted aliphatic hydrocarbons. When the alcohols and ketones of hexane and octane were tested against lung BzOPh'ase activity, I50 values ranged from 16 microM (1-octanol) to 4.8 mM (2,5-hexanedione). Lung EtOPh'ase activity exhibited some sensitivity towards the alcohols and ketones, and I50 values ranged from 0.52 mM (4-octanol) to 40.5 mM (2-hexanol). The data show rat lung BzOPh'ase and EtOPh'ase activities are differentially sensitive towards the selected unsubstituted aliphatic hydrocarbons and corresponding alcohols and ketones. The difference in sensitivities may reflect different requirements for an adventitious interaction between a hydrocarbon and enzyme active site.
Rabovsky
J
J
Division of Respiratory Disease Studies, National Institute for Occupational Safety and Health, Morgantown, WV 26505.
Judy
D J
DJ
D000438:Alcohols / Q000494:pharmacology*; D000473:Alkanes / Q000494:pharmacology*; D000818:Animals; D019362:Cytochrome P-450 CYP2B1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D007659:Ketones / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008861:Microsomes / Q000201:enzymology; D010088:Oxidoreductases / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship
D000438:Alcohols; D000473:Alkanes; D007659:Ketones; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019362:Cytochrome P-450 CYP2B1