Toxicity xenobiotic-metabolizing human cell

Calu-3 cells have shown the ability to perform fatty acid esterification of budes-onide [132], In pre-clinical studies, this esterification results in a prolonged local tissue binding and efficacy, which is not found when the esterification is inhibited [133]. The precise mechanism remains undefined in that the identity of specific enzyme(s) responsible for this metabolic reaction is unclear [134], Assessment of the potential toxicity and metabolism of pharmaceuticals and other xenobiotics using in vitro respiratory models is still at its infancy. The development of robust in vitro human models (i.e., cell lines from human pulmonary origin) has the potential to contribute significantly to better understanding the role of biotransformation enzymes in the bioactivation/detoxication processes in the lung. 

Absorption, Distribution, Metabolism, Excretion. Examination of Section 2.6 clearly indicates that oral administration of NDMA has been the preferred route for studying its absorption, distribution, metabolism and excretion. This is not surprising since oral administration is easier to monitor when compared to other routes. The oral route seems to be the most pertinent to study since humans are most likely to be exposed to nitrosamines orally. Toxicokinetic data with regard to dermal and inhalation exposure of NDMA are clearly lacking. Furthermore, dermal and inhalation exposures may lead to different metabolic pathways and patterns of distribution and excretion, which could account for differences in the degree of toxicity exhibited by different routes of exposure. The metabolism of NDMA in isolated microsomal preparations seems to be well understood, but studies with cultured human cells could provide additional useful information. However, exploration of the denitrosation mechanism as an alternative to a-hydroxylation requires more attention. Determination of the urinary excretion of NDMA in control human volunteers and in individuals known to consume foods with high contents of nitrosamines could provide information concerning absorption and excretion of the xenobiotic. 

Despite the scarcity of direct evidence, HA is generally believed to be present as a metabolic intermediate in mammalian tissues Recent studies on the reductive detoxification of HAs both by human NADH-cytochrome i>5 reductase and by human cytochrome b5 may be considered as additional supporting evidence for the in vivo formation of HA in mammalian cells that needs to be controlled in order to avoid the toxic effects of an excess of endogenously produced HA, as well as of HA produced by detoxification of xenobiotic HA derivatives " . 

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