Xenobiotica. 1985 May;15(5):369-79.  

Selective inhibitory interactions of alkoxymethylenedioxybenzenes towards
mono-oxygenase activity in rat-hepatic microsomes.

Murray M, Hetnarski K, Wilkinson CF.

A series of eight 4-n-alkoxymethylenedioxybenzene (AMDB) derivatives were
evaluated for their inhibitory effects on several mono-oxygenase reactions and
their capacity to form metabolite complexes with cytochrome P-450 in vitro in
hepatic microsomes from phenobarbital (PB)-and Beta-naphthoflavone (Beta
NF)-induced rats. Ethoxyresorufin O-deethylase in Beta NF-induced microsomes and
aminopyrine N-demethylase in PB-induced microsomes were most susceptible to
inhibition by the test compounds. In contrast, aldrin epoxidation and
arylhydrocarbon hydroxylase in PB-and Beta NF-induced microsomes, respectively,
were not inhibited by derivatives of AMDB. All AMDB derivatives elicited
spectral complexes with cytochrome P-450, the characteristics of which were
influenced by the microsomes employed and by the length of the AMDB alkoxy
side-chain. Derivatives containing short-chain alkoxy substituents (C1 to C3)
formed unstable metabolite complexes and generated substantial quantities of
carbon monoxide (CO), those with intermediate length alkoxy groups (C4 to C6)
generated little CO and rapidly formed intense spectral complexes (large delta A
max), and those with the largest alkoxy groups (C7 and C8) formed no CO and
elicited complexes of high stability. Quantitative structure-activity analyses
showed that the biological data could be described by parabolic equations in II,
the hydrophobic constant of the alkoxy substituent, and suggested the importance
to AMDB interactions of a lipophilic-binding region at the active centre of the
cytochrome P-450. The alkoxy chain length for optimal mono-oxygenase inhibition
and complex formation with cytochrome P-450 appeared to be about five or six
carbon atoms. The data suggest that the capacity of AMDB compounds to form
stable inhibitory complexes with cytochrome P-450 may not always be associated
with their ability to inhibit mono-oxygenase activity.

PMID: 4036165 [PubMed - indexed for MEDLINE]