Monoxygenase inhibition

Isolated lettuce chloroplasts could epoxidize zeaxanthin in the presence of reduced pyridine nucleotides and oxygen and the process was stimulated by bovine serum albumin (which protected the epoxidase system from inhibition by fatty acids). Detailed study led to the conclusion that the epoxidase was an external monoxygenase and that the violaxanthin cycle (of which epoxidation of zeaxanthin is a part) was a trans-membrane system wherein de-epoxidation took place on the loculus side and epoxidation on the stroma side of the membrane. This arrangement requires migration of the carotenoids of the violaxanthin cycle across the membrane in a type of shuttle. The possible role of this cycle in some regulatory mechanism of photosynthesis at the membrane level was also discussed. 

The biosynthesis of the isoprenoid moiety of terpenoid alkaloids has been reviewed. It has been found ° that catharanthine (which accumulates in Vinca rosea) inhibited a membrane-bound monoxygenase that oxidized geraniol at C-10. The inhibition was reversible and non-competitive in solubilized preparations of the enzyme and hence was probably not due to disruption of membranes. Other alkaloids that were produced as end-products were less inhibitory and catharanthine may mediate feed-back control of alkaloid biosynthesis in vivo. 

Data on competitive inhibitions provide corroborative evidence for the presence of more than one monoxygenase in microsomal membranes.27-29 Although a number of cytochrome monoxygenases thus appear to be present in liver, each enzyme probably can accept a variety of substrates and each is capable of catalyzing various oxidative transformations including epoxidations, aryl and alkyl hydroxylations and oxidations at nitrogen and sulfur. 

Criteria for the involvement of the P-450 system in the metabolism of specific drugs or xenobiotlc compounds include i) enhancement of metabolism after pretreatment of animals with phenobarbltal and in some instances after treatment with polycyclic aromatic hydrocarbons ii) localization of enzyme activity in microsomal fractions with high levels present in liver lii) inhibition by carbon monoxide piperonylbutoxide P-diethylaminoethyl-3 3-diphenylpropylacetate (SKF 325a) and certain other compounds iv) requirement for NADPH as a source of reducing equivalents. The follov ng sections provide representative exaiq>les of types of drug metabolism which appear to be catalyzed by P-450 monoxygenases. 

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