Mammalian systems, electronic properties

Recent work in our laboratories has confirmed the existence of a similar pathway in the oxidation of vindoline in mammals (777). The availability of compounds such as 59 as analytical standards, along with published mass spectral and NMR spectral properties of this compound, served to facilitate identification of metabolites formed in mammalian liver microsome incubations. Two compounds are produced during incubations with mouse liver microsome preparations 17-deacetylvindoline, and the dihydrovindoline ether dimer 59. Both compounds were isolated and completely characterized by spectral comparison to authentic standards. This work emphasizes the prospective value of microbial and enzymatic transformation studies in predicting pathways of metabolism in mammalian systems. This work would also suggest the involvement of cytochrome P-450 enzyme system(s) in the oxidation process. Whether the first steps involve direct introduction of molecular oxygen at position 3 of vindoline or an initial abstraction of electrons, as in Scheme 15, remains unknown. The establishment of a metabolic pathway in mammals, identical to those found in Strep-tomycetes, with copper oxidases and peroxidases again confirms the prospective value of the microbial models of mammalian metabolism concept. 

This similar dependence of in vivo potency and mustard reactivity on substituent electronic properties (cf Equations I and 4) has been cited (8) as evidence that the biological activity of these compounds is directly due to the rate at which they alkylate cellular DNA. However, in complex in vivo systems the possible roles of drug transport and metabolism as well as DNA repair have also to be considered. Surprisingly, there is virtually no quantitative data available on the cytotoxicity of substituted aniline mustards in mammalian cell culture systems, where the effects of substituent electronic effects on cytotoxicity and stability can be examined in the... 

B. Mammalian Systems. Investigations of the electronic properties of plant systems served as an excellent entree into the examination of mammalian membranes using the techniques already developed. Because of the writer s long-time interest in muscle physiology, this tissue was chosen for exploration with the objective of obtaining more intimate information regarding muscle behavior. 

The formation of succinate from fumarate by fumarate reductase (FR) and anaerobic phosphorylation of ADP to ATP are amongst the important reactions taking place in the mitochondria to provide energy to the helminths. The FR system of helminths differs from succinate dehydrogenase (SDH) of mammalian tissues in several ways. For example (a) FR requires NAD while SDH utilizes flavin nucleotide (FAD) as the coenzyme (b) FR acts only in one direction but SDH is a reversible enzyme (c) FR acts as the terminal electron acceptor under anaerobic conditions while SDH has no such property. Levamisole was shown to inhibit the FR in Ascaris [43]. 

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