Oxidative metabolism slowing down

Long-chain fatty acids can slowly cross the mitochondrial membrane by themselves, but this is too slow to keep up with their metabolism. The carnitine shuttle provides a transport mechanism and allows control of (3 oxidation. Malonyl-CoA, a precursor for fatty acid synthesis, inhibits the carnitine shuttle and slows down (3 oxidation (Fig. 13-5). 

MAO-inhibitors are chemical compounds whose activity in the body slows down or interferes with Mono Amine Oxidase, an enzyme system that oxidizes many compounds in foods and drugs into harmless byproducts. In the presence of MAO-inhibitors, compounds that would normally be metabolized into inactive by-products instead have the duration of their physiological and psychological activity extended. 

Fig. 14. Enhancement of plasma concentration by slowing down the oxidative metabolism of a muscarinic anaigesic [53],...

The oxidative metabolism leads to the formation of reactive species (epoxides, quinone-imines, etc.), which can be a source of toxicity. Consequently, slowing down or limiting these oxidations is an important second target in medicinal chemistry. Thus, the metabolism of halothan (the first modern general anaesthetic) provides hepatotoxic metabolites inducing an important rate of hepatitis the oxidation of the non-fluorinated carbon generates trifluoroacetyl chloride. The latter can react with proteins and lead to immunotoxic adducts [54], The replacement of bromine or chlorine atoms by additional fluorine atoms has led to new families of compounds, preferentially excreted by pulmonary way. These molecules undergo only a very weak metabolism rate (1-3%) [54,55]. 

The TD-induced inhibition of metabolic flux through PDHC takes place in all cells of the affected organism (Jankowska-Kulawy et al. 2010). It causes primary inhibition of acetyl-CoA synthesis in the mitochondria, yielding a proportional reduction of its metabolic flux through first steps of the TCA cycle and further aggravation of this suppression due to inhibition of KDHC (Jankowska-Kulawy et al. 2010 Shi et al. 2007) (Figure 33.1). As a result, oxidative phosphorylation process slows down, yielding ATP deficits (Jhala and Hazell 2011). 

---