Transport hepatocyte membrane

Konig, J., et al. A novel human organic anion transporting polypeptide localized to the basolateral hepatocyte membrane. Am. J. Physiol. 2000, 278, G156-G164. 

As mentioned above, the liver has a dual blood supply. The hepatic artery delivers material from the systemic circulation and the portal blood flow delivers directly from the gastrointestinal system. The portal system is involved in the first pass effect , where the nutrients and xenobiotics that are absorbed from the stomach and intestines are filtered through the liver before reaching the systemic circulation (Treinen-Moslen, 2001). The space of Disse allows close contact between circulating plasma, plasma proteins, and hepatocytes, allowing for rapid diffusion of lipophilic compounds across the hepatocyte membrane. Some compounds are specifically taken up by sinusoidal transporters, including... 

Hydrophilic xenobiotics enter the cell at the sinusoidal side of the hepatocyte membrane by means of transport systems using carrier proteins. These carrier proteins exhibit no or only low substrate specificity, so that various endogenous and also exogenous substances can be transported through the cell membrane. Competition between these substances for carrier proteins may lead to the mutual inhibition of the transport mechanism. 

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. 

Bile formation occurs by processes that are not hilly defined. It takes place in canaliculi, minute passages lined by specialized modihcations of the hepatocyte membrane, that ultimately unite to form bile ductules. Hepatic bile contains 5% to 15% total solids, the major component of which is bile acids. The increase in biliary water and electrolyte excretion caused by this osmotic effect represents the bile acid-dependent fraction of bile flow. Even with severe depletion of the circulating bile acid pool, as is seen with bile duct diversion, some bile flow continues. The active transport of sodium and of glutathione and bicarbonate is mediated by Na-K-ATPase, which is responsible for the bile acid-independent flow of bile (up to 40% of total flow). Hormones such as secretin increase bile flow by stimulating secretion of sodium, bicarbonate, and chloride. Hormone-dependent flow accounts for 20% to 25% of the total. 

Figure 9.9 Transport systems participating in drug transport in hepatocyte membranes.

Table 9,3 Hepatic transport systems and their localization in hepatocyte membranes.

An important first step in the hepatic metabolism of proteins and peptides is the uptake into hepatocytes. Small peptides may cross the hepatocyte membrane via passive diffusion if they have sufficient hydrophobicity. Uptake of larger peptides and proteins is facilitated via various carrier-mediated, energy-dependent transport processes. Receptor-mediated endocytosis is an additional mechanism for uptake into hepatocytes (see Sect. 8.3.4.5) [28]. In addition, peptides such as metkephamid can already be metabolized on the surface of hepatocytes or endothelial cells [41]. 

The IC50 and of transporter inhibitors can be determined using selective transporter substrate by in vitro assays. For uptake transporters, hepatocyte, transporter transfected cells, oocytes, and yeast have been used as in vitro models for efflux transporter, Caco-2 cells, and transporter transfected cells and membranes are commonly used models. 

The findings of the present investigation indicate that the K , value for hepatic taurocholate uptake significantly increases at birth in the rabbit. This observed increase in K , indicates that the overall efficiency of hepatic uptake of taurocholate decreases at birth. Conceptually, this observed change in can be attributed to two factors (a) alterations in the hepatocyte membrane to affect carrier conformation and mobility (b) structural modifications in the carrier protein. Recent studies by Benz et al. (1977) on the influence of membrane structure on carrier-mediated transport demonstrated that the translocation rate constant or K,n is strongly dependent on the nature of the membrane structure. 

The insulin receptor is a transmembrane receptor tyrosine kinase located in the plasma membrane of insulin-sensitive cells (e.g., adipocytes, myocytes, hepatocytes). It mediates the effect of insulin on specific cellular responses (e.g., glucose transport, glycogen synthesis, lipid synthesis, protein synthesis). 

In rat liver mitochondria, in state 4, the AP was estimated to be about 220 mV, with the membrane potential representing about 90% of this (Nicholls, 1974 Appendix 3). Similar values have been reported for human and rat skeletal muscle mitochondria in state 4 (Stumpf et al., 1982). The control of the rate of electron transport is not only determined by the availability of ADP, but also of Pj oxidizable substrates, and oxygen. There is evidence for futile cycling of protons in intact normal rat hepatocytes (Brand et al., 1993). Recently, Porter and Brand (1993) found a correlation between the proton permeability of the inner membrane of liver mitochondria and body size in animals from the mouse (20 g) to horses (150 kg) with a decrease in permeability with increasing weight of several-fold at a constant... 

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