Cellular detoxification process

Since both Phase I and II biotransformation processes can increase the polarity and, accordingly, the aqueous solubility of the toxicant, these biotransformations can essentially trap the toxicant in the cell by compromising its ability to passively diffuse across the surface membrane of the cell. The cellular elimination of toxicants is facilitated by membrane proteins that actively transport Phase I and II biotransformation products out of the cell and make them available for elimination from the body. The active cellular elimination processes are often referred to as Phase III detoxification/elimination processes. 

Conjugation of lipophilic xenobiotics to polar cellular constituents renders the xenobiotic more water-soluble. While the lipophilic parent xenobiotics could readily diffuse into the cells, the increase in polarity associated with conjugation greatly reduces the ability of the compound to diffuse across the lipid bilayer of the cell membrane thus trapping the compound within the cell. The polar conjugates must therefore rely upon active transport processes to facilitate efflux from the cell. Hepatocytes, as well as other cells involved in chemical detoxification, are rich with members of the ATP-binding cassette superfamily of active transport proteins (ABC transporters). Cellular efflux of xenobiotics by these transporters is often referred to as Phase III elimination because Phase I or II detoxification processes often precede and are a requirement of Phase III elimination. A detailed description and discussion of elimination and transporters is presented in Chapter 15. 

Ciclosporin can cause cholestasis and cellular necrosis by an inhibitory effect on hepatocyte membrane transport proteins at both sinusoidal and canalicular levels. It induces oxidative stress by accumulation of various free radicals. Ademetionine (5-adenosylmethionine) is a naturally occurring substance that is involved in liver detoxification processes. The efficacy of ademetionine in the treatment and prevention of ciclosporin-induced cholestasis has been studied in 72 men with psoriasis (89). The patients who were given ciclosporin plus ademetionine had low plasma and erythrocyte concentrations of oxidants and high concentrations of antioxidants. The authors concluded that ademetionine may protect the hver against hepatotoxic substances such as ciclosporin. 

The biodistribution of CN to various systemic tissues will determine the relative proportions of CN present at detoxification and target tissue or cellular sites. For example, inhaled or percutaneously absorbed CN enters the systemic circulation and only a small proportion of the absorbed dose will be available for first-pass detoxification, particularly in the liver. In contrast, a high proportion of a p.o. dose will pass through the liver and be available for first-pass detoxification. However, hepatic detoxification processes may be complex, since it has been demonstrated that dietary variations that cause alterations in hepatic sulfurtransferase activity do not correlate with CN toxicity (Rutkowski et ah, 1985), and extensive chemical or surgical injury to the liver does not increase the susceptibility of the mouse to CN toxicity (Rutkowski et ah, 1986). The influence of route on toxicity is probably due to the relative effects of plasma transulfuration, sequestration by erythrocytes, intracellular macromolecular binding, and the differential distribution to all tissues with a detoxification capacity. 

Cellular Processes Cell division Chaperones Detoxification... 

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