Liver alanine

The skeletal muscle is the most important site for degradation of the branched-chain amino acids (Val, Leu, lie see p. 414), but other amino acids are also broken down in the muscles. Alanine and glutamine are resynthesized from the components and released into the blood. They transport the nitrogen that arises during amino acid breakdown to the liver (alanine cycle see above) and to the kidneys (see p. 328). 

Glucocorticoids also increase the activity of transaminases (aminotransferases), especially in the skeletal muscle. Aminotransferases serve to transfer the amino groups from amino acids to be metabolized to a-keto acids, especially pyruvate. In the latter case, the alanine thus formed is transported from the muscle into the bloodstream and extracted from there by the liver. In the liver, alanine is converted to glucose, and glucose may then return to the muscle as it does in the Cori cycle (Figure 18.4). This is the alanine cycle, and more about this is discussed in Chapter 20. Branched-chain amino acids are the principal donors of nitrogen to pyruvate in the muscle and are thus important actors in the alanine cycle. 

Figure 20-4. Biochemical pathways for gluconeogenesis in the liver. Alanine, a major gluconeogenic substrate, is used to synthesize oxaloacetate. The carbon skeletons of glutamine and other glucogenic amino acids feed into the TCA cycle as a-ketoglutarate, succinyl-CoA, fumarate, or oxaloacetate and thus also provide oxaloacetate. Conversion of oxaloacetate to phosphoenolpyruvate and ultimately to glucose limits the availability of oxaloacetate for citrate synthesis and thus greatly diminishes flux through the initial steps of the TCA cycle (dashed lines). Concurrent P-oxidation of fatty acids provides reducing equivalents (NADH and FADH2) for oxidative phosphorylation but results in accumulation of acetyl-CoA.

Alternatively, in skeletal muscle, pyruvate can be transaminated to alanine (which affords a route for nitrogen transport from muscle to liver) in the liver alanine is used to regenerate pyruvate, which can then be diverted into gluconeogenesis. This process is referred to as the glucose-alanine cycle. 

Figure 23.15. The Alanine Cycle. Glutamate in muscle is transaminated to alanine, which is released into the bloodstream. In the liver, alanine is taken up and converted into pyruvate for subsequent metabolism. 

Alanine aminotransferase (second most active in liver) Alanine + 2-Oxoglutarate (a-kitoglutarate) n Pyruvate + Glutamate... 

Alanine is formed from pyruvate in muscle. After it is transported to the liver, alanine is reconverted to pyruvate by alanine transaminase. Eventually pyruvate is used in the synthesis of new glucose. Because muscle cannot synthesize urea from amino nitrogen, the glucose-alanine cycle is used to transfer amino nitrogen to the liver. 

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... 

Older adults are particularly susceptible to a potentially fatal hepatitis when taking isoniazd, especially if they consume alcohol on a regular basis. Two other antitubercular drugs rifampin and pyrazinamide, can cause liver dysfunction in the older adult. Careful observation and monitoring for signs of liver impairment are necessary (eg, increased serum aspartate transaminase, increased serum alanine transferase, increased serum bilirubin, and jaundice). 

When administering tacrine, the nurse must monitor the patient for liver damage. This is best accomplished by monitoring alanine aminotransferase (AIT) levels. ALT is an enzyme found predominately in the liver. Disease or injury to the liver causes a release of tiiis enzyme into the bloodstream, resulting in elevated ALT levels, hi patients taking tacrine, ALT levels should be obtained weekly from at least week 4 to week 16 after die initiation of tiierapy. After week 16, transaminase levels are monitored every 3 months. 

The choice of IFN-a as a potential treatment for chronic hepatitis C in 1986 was empirical (Hoofnagle et al. 1986). At this time, the causative agent of chronic non-A, non-B hepatitis had not yet been identified, and there was no way of evaluating HCV replication or, thus, the antiviral activity of a drug. In the first cohort of 10 patients with chronic non-A, non-B hepatitis treated with IFN-a, a significant decline in alanine aminotransferase (ALT) levels was observed in 8 patients, and liver histology had improved at the end of therapy in the three patients who were biopsied (Hoofnagle et al. 1986). Ten years later, 5 of the 10 patients were free of infection (Lau et al. 1998). 

Major amino acids emanating from muscle are alanine (destined mainly for gluconeogenesis in liver and forming part of the glucose-alanine cycle) and glutamine (destined mainly for the gut and kidneys). 

Use of zileuton is uncommon due to the need for dosing four times a day, potential drug interactions, and the potential for hepatotoxicity with the resulting need for frequent monitoring of liver enzymes. In patients started on zileuton, serum alanine aminotransferase concentrations should be monitored before treatment begins, monthly for the first 3 months, every 2 to 3 months for the remainder of the first year, and then periodically thereafter for as long as the patient continues to receive the medication. Zileuton also inhibits the cytochrome P-450 (CYP) mixed function enzyme system and has been shown to decrease the clearance of theophylline, R-warfarin and propranolol.34... 

Hepatocellular damage manifests as elevated serum aminotransferases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)]. The degree of transaminase elevation does not correlate with the remaining functional metabolic capacity of the liver. An AST level two-fold higher than ALT is indicative of alcoholic liver damage. 

Tolcapone has been associated with several cases of severe liver failure, including fatalities, and has been removed from the market in some countries. Thus, it should only be used in patients who cannot take or do not respond to entacapone. Serum alanine aminotransferase and aspartate aminotransferase concentrations should be monitored at baseline, then every 2 to 4 weeks for 6 months, and then periodically for the remainder of therapy. Patients who fail to show symptomatic benefit after 3 weeks should discontinue tolcapone. Entacapone has not been associated with liver damage, so monitoring of liver enzymes is not currently recommended.24,25,29... 

Major adverse events Edema, weight gain disconti nue use if alanine aminotranferase (ALT) greater than 3 times normal monitor liver function tests at baseline and periodically thereafter ... 

A few cases of hepatotoxicity have been reported with rosiglitazone and pioglitazone, but no serious complications have been reported, and symptoms typically reverse within several weeks of discontinuing therapy. Therefore, periodic liver function tests should be performed at baseline and during thiazolidinedione therapy. Patients with a baseline alanine aminotransferase (ALT) level greater than 2.5 times the upper limit of normal should not receive a TZD. If ALT levels rise to greater than 3 times the upper limit of normal in patients receiving a TZD, the medication should be discontinued. 

TC, lamivudine ABC, abacavir APV, amprenavir AST, aspartate aminotransferase ALT, alanine aminotransferase ATV, atazanavir CBC, complete blood cell count D/C, discontinue ddl, didano-sine d4T, stavudine EFV, efavirenz FTC, emtricitabine P1BV, hepatitis B virus F1CV, hepatitis C vims HIV, human immunodeficiency virus IDV, indinavir IV, intravenous LFT, liver function tests LPV/r, lopinavir + ritonavir NNRTI, nonnucleoside reverse transcriptase inhibitor NRTI, nucleoside reverse transcriptase inhibitor NVP, nevirapine PI, protease inhibitor PT, prothrombin time T.bili, total bilirubin TDF, tenofovir disoproxiI fumarate TPV, tipranavir ULN, upper limit of normal ZDV, zidovudine. 

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