Liver substrate inhibition

Mechanisms of drug uptake in liver slices were studied in vitro as early as in 1963 by Schanker and Solomon [89]. The results obtained in these experiments are still valuable and show that the influence of temperature, anoxia, metabolic inhibitors and substrate inhibition can be successfully studied in this preparation. However, as mentioned before, at that time the preparation of reproducible precision-cut slices was not feasible. Therefore, the slice incubation technique was virtually abandoned in transport studies after the introduction of the successful isolation of rat hepatocytes. 

K. Fluiter and T. J. C. Van Berkel, Scavenger receptor B1 (SR- Bl) substrates inhibit the selective uptake of high-density-lipoprotein cholesteryl esters by rat parenchymal liver cells, Biochem. J. 326 515-519 (1997). 

GRAPEFRUIT JUICE TALINOLOL Significant risk of 1 therapeutic effects Talinolol is a substrate of P-gp, and less than 1 % is metabolized in the liver. However, inhibition by grapefruit juice of an intestinal uptake process other than P-gp is considered likely Do not co-administer... 

D-Fructose 1,6-diphosphatases from rabbit liver and muscle are similar in their cation-requirement profile, molecular weight, substrate affinity, and substrate inhibition, but have different amino acid compositions, and the muscle enzyme does not cross-react with antibody to the purified liver-enzyme.361,364 The muscle enzyme is more sensitive to AMP than the enzyme from liver or kidney.385... 

Substrate inhibition of bovine liver glutamate dehydrogenase has not been studied in such detail. It is most marked when the NAD(P) concentration is also large (11), and is relieved by ADP. This appears to be the reason why ADP activates the enzyme when large glutamate and... 

When Rudolph and Fromm used thionicotinamide adenine dinucleotide (thio-DPN) as an alternate substrate for NAD+ and varied the concentration of ethanol with liver alcohol dehydrogenase [following the reaction at 342 nm, the isosbes-tic point for thio-DPN and reduced thio-DPN (thio-DPNH)], they saw what appeared to be concave upward reciprocal plots with partial substrate inhibition in the presence of thio-DPN (38). However, the asymptote intercepts appeared to decrease with increased thio-DPN concentration, which is not what the above equations predict for a case where a minimum is present in the curve. There must have been other interactions that caused the substrate inhibition by ethanol in the presence of thio-DPN. 

Competitive substrate inhibition of an enzyme isolated from human liver by ion-exchange chromatography showed that it hydrolysed a-L-arabinosides, jS-D-galactosides, -D-glucosides, jS-D-fucosides, and jS-D-xylosides. Another... 

Pyruvate kinase possesses allosteric sites for numerous effectors. It is activated by AMP and fructose-1,6-bisphosphate and inhibited by ATP, acetyl-CoA, and alanine. (Note that alanine is the a-amino acid counterpart of the a-keto acid, pyruvate.) Furthermore, liver pyruvate kinase is regulated by covalent modification. Flormones such as glucagon activate a cAMP-dependent protein kinase, which transfers a phosphoryl group from ATP to the enzyme. The phos-phorylated form of pyruvate kinase is more strongly inhibited by ATP and alanine and has a higher for PEP, so that, in the presence of physiological levels of PEP, the enzyme is inactive. Then PEP is used as a substrate for glucose synthesis in the pathway (to be described in Chapter 23), instead... 

Atovaquone, a hydroxynaphthoquinone, selectively inhibits the respiratory chain of protozoan mitochondria at the cytochrome bcl complex (complex III) by mimicking the natural substrate, ubiquinone. Inhibition of cytochrome bcl disrupts the mitochondrial electron transfer chain and leads to a breakdown of the mitochondrial membrane potential. Atovaquone is effective against all parasite stages in humans, including the liver stages. 

In the case of dmg interactions involving metabolic inhibition, little increase in the substrate concentration is expected when the inhibition constant (K ) determined in in vitro studies using human liver samples is larger than the inhibitor concentration in vivo. Various approaches have been adopted using mathematical models in attempts to quantitatively predict in vivo dmg interactions from in vitro data [5]. 

The rate of mitochondrial oxidations and ATP synthesis is continually adjusted to the needs of the cell (see reviews by Brand and Murphy 1987 Brown, 1992). Physical activity and the nutritional and endocrine states determine which substrates are oxidized by skeletal muscle. Insulin increases the utilization of glucose by promoting its uptake by muscle and by decreasing the availability of free long-chain fatty acids, and of acetoacetate and 3-hydroxybutyrate formed by fatty acid oxidation in the liver, secondary to decreased lipolysis in adipose tissue. Product inhibition of pyruvate dehydrogenase by NADH and acetyl-CoA formed by fatty acid oxidation decreases glucose oxidation in muscle. 

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