Hepatic acetylation

Inactivation and Removal of Viruses. In developing methods of plasma fractionation, the possibiHty of transmitting infection from human vimses present in the starting plasma pool has been recognized (4,5). Consequentiy, studies of product stabiHty encompass investigation of heat treatment of products in both solution (100) and dried (101) states to estabHsh vimcidal procedures that could be appHed to the final product. Salts of fatty acid anions, such as sodium caprylate [1984-06-17, and the acetyl derivative of the amino acid tryptophan, sodium acetyl-tryptophanate [87-32-17, are capable of stabilizing albumin solutions to 60°C for 10 hours (100) this procedure prevents the transmission of viral hepatitis (102,103). The degree of protein stabilization obtained (104) and the safety of the product in clinical practice have been confirmed (105,106). The procedure has also been shown to inactivate the human immunodeficiency vims (HIV) (107). 

Intestinal absorption of digoxin is less complete compared to digitoxin. In order to improve absorption, acetylated- and methylated-digoxin derivates were developed. Digitoxin is metabolised in hepatic microsomal enzymes and can be cleared independently from renal function. The therapeutical serum level of digoxin is 0.5-2.0 ng/ml and 10-35 ng/ml of digitoxin. Steady state plateau of therapeutic plasma concentrations is reached after 4-5 half-life-times using standard daily doses [5]. 

The citric acid cycle is the final common pathway for the aerobic oxidation of carbohydrate, lipid, and protein because glucose, fatty acids, and most amino acids are metabolized to acetyl-CoA or intermediates of the cycle. It also has a central role in gluconeogenesis, lipogenesis, and interconversion of amino acids. Many of these processes occur in most tissues, but the hver is the only tissue in which all occur to a significant extent. The repercussions are therefore profound when, for example, large numbers of hepatic cells are damaged as in acute hepatitis or replaced by connective tissue (as in cirrhosis). Very few, if any, genetic abnormalities of citric acid cycle enzymes have been reported such ab-normahties would be incompatible with life or normal development. 

FIGURE 9. Endogenous lipoprotein metabolism. In liver cells, cholesterol and triglycerides are packaged into VLDL particles and exported into blood where VLDL is converted to IDL. Intermediate-density lipoprotein can be either cleared by hepatic LDL receptors or further metabolized to LDL. LDL can be cleared by hepatic LDL receptors or can enter the arterial wall, contributing to atherosclerosis. Acetyl CoA, acetyl coenzyme A Apo, apolipoprotein C, cholesterol CE, cholesterol ester FA, fatty acid HL, hepatic lipase HMG CoA, 3-hydroxy-3-methyglutaryl coenzyme A IDL, intermediate-density lipoprotein LCAT, lecithin-cholesterol acyltransferase LDL, low-density lipoprotein LPL, lipoprotein lipase VLDL, very low-density lipoprotein. 

Three compounds acetoacetate, P-hydroxybutyrate, and acetone, are known as ketone bodies. They are suboxidized metabolic intermediates, chiefly those of fatty acids and of the carbon skeletons of the so-called ketogenic amino acids (leucine, isoleucine, lysine, phenylalanine, tyrosine, and tryptophan). The ketone body production, or ketogenesis, is effected in the hepatic mitochondria (in other tissues, ketogenesis is inoperative). Two pathways are possible for ketogenesis. The more active of the two is the hydroxymethyl glutarate cycle which is named after the key intermediate involved in this cycle. The other one is the deacylase cycle. In activity, this cycle is inferior to the former one. Acetyl-CoA is the starting compound for the biosynthesis of ketone bodies. 

Ketosis is a pathologic state produced by an excess of ketone bodies in the organism. However, ketosis may be regarded as a lipid metabolism pathology with a certain reserve, since excessive biosynthesis of ketone bodies in the liver is sequent upon an intensive hepatic oxidation not only of fatty acids, but also of keto-genic amino acids. The breakdown of the carbon frameworks of these amino acids leads to the formation of acetyl-CoA and acetoacetyl-CoA, which are used in... 

Although aminoacyl-tRNA synthetases are necessary for protein synthesis in all tissues, their importance in chemical carcinogenesis is difficult to assess. Mutation induction by this pathway has been studied extensively (123), yet metabolic activation in a carcinogen-target tissue has not been demonstrated. The only exception is hepatic prolyl-tRNA synthetase activation of N-hydroxy-Trp-P-2 however, hepatic O-acetylation of this substrate also occurs to an appreciable extent (12). Further investigations involving the use of specific enzyme inhibitors would be helpful in addressing this problem. 

Manno et al. [43] observed the formation of superoxide during the oxidation of arylamines by rat liver microsomes. Noda et al. [44] demonstrated that microsomes are able to oxidize hydrazine into a free radical. In contrast, hepatic cytochrome P-450 apparently oxidizes paracetamol (4 -hydroxyacetanilide) to A-acetyl-p-benzoquinone imine by a two-electron mechanism [45]. Younes [46] proposed that superoxide mediated the microsomal S -oxidation of thiobenzamide. 

The answer is b. (Hardman, pp 868 869.) Persons with low hepatic iY-acetyltransferase activity are known as slow acetylators. A major pathway of metabolism of procainamide, which is used to treat arrhythmias, is iV-acetylation. Slow acetylators receiving this drug are more susceptible than normal persons to side effects, because slow acetylators will have higher-than-normal blood levels of these drugs N-acetylprocainamide, the metabolite of procainamide, is also active. 

Hydralazine may cause a dose-related, reversible lupus-like syndrome, which is more common in slow acetylators. Lupus-like reactions can usually be avoided by using total daily doses of less than 200 mg. Other hydralazine side effects include dermatitis, drug fever, peripheral neuropathy, hepatitis, and vascular headaches. For these reasons, hydralazine has limited usefulness in the treatment of hypertension. However, it may be useful in patients with severe chronic kidney disease and in kidney failure. 

Because of its involvement with many aspects of lipid metabolism so far described, it will be apparent from the discussion so far that acetyl-CoA is an axle around which hepatic lipid metabolism revolves. Indeed, acetyl-CoA links lipid and carbohydrate metabolism. Figure 6.20 summarizes the central role of acetyl-CoA in lipid related pathways in the liver. 

When taken in therapeutic doses (approximately 4 g 60mg/kg body weight) paracetamol (N-acetyl-para-ami nophenol, acetaminophen) is a safe and effective analgesic, but overdosage, possibly with the intent of self-harm, is a major cause of drug-induced hepatic toxicity. The cellular damage which may not be evident for up to... 

Interesting information stems from studies of the hepatotoxic effect of the concomitant administration of rifampicin, another antituberculostatic drug (and a potent inducer of cytochrome P450) often used in combination with isoniazid. Rifampicin alone is not hepatotoxic but increases significantly the incidence of hepatitis in patients simultaneously dosed with isoniazid. In human volunteers (6 slow and 8 rapid acetylators), daily administration of rifampicin increased the release of hydrazine from isoniazid [180], In slow acetylators, the proportion of the dose metabolized to hydrazine increased... 

J. R. Mitchell, U. P. Thorgiersson, M. Black, J. A. Timbreb, W. R. Snodgrass, W. Z. Potter, D. J. Jollow, H. Keiser, Increased Incidence of Isoniazid Hepatitis in Rapid Acetylators Possible Relation to Hydrazine Metabobtes , Clin. Pharmacol. Ther. 1975, 18, 70-79. 

Formed from excess hepatic acetyl CoA during fasting acetoacetate, 3-hydroxybutyrate, and acetone (not metabolized further)... 

Isoniazid is bactericidal against growing M. tuberculosis. Its mechanism of action remains unclear. (In the bacterium it is converted to isonicotinic acid, which is membrane impermeable, hence likely to accumulate intracellu-larly.) Isoniazid is rapidly absorbed after oral administration. In the liver, it is inactivated by acetylation, the rate of which is genetically controlled and shows a characteristic distribution in different ethnic groups (fast vs. slow acetylators). Notable adverse effects are peripheral neuropathy, optic neuritis preventable by administration of vitamin Be (pyridoxine) hepatitis, jaundice. 

An alternative form of p-oxidation takes place in hepatic peroxisomes, which are specialized for the degradation of particularly long fatty acids (n > 20). The degradation products are acetyl-CoA and hydrogen peroxide (H2O2), which is detoxified by the catalase (see p. 32) common in peroxisomes. 

Pharmacokinetics Hydralazine is rapidly absorbed after oral use. Half-life is 3 to 7 hours. Protein binding is 87%, and bioavailability is 30% to 50%. Plasma levels vary widely among individuals. Peak plasma concentrations occur 1 to 2 hours after ingestion duration of action is 6 to 12 hours. Hypotensive effects are seen 10 to 20 minutes after parenteral use and last 2 to 4 hours. Slow acetylators generally have higher plasma levels of hydralazine and require lower doses to maintain control of blood pressure. Hydralazine undergoes extensive hepatic metabolism it is excreted in the urine as active drug (12% to 14%) and metabolites. 

As an example, acetaminophen (APAP) in overdose has been used by several groups to identify hepatotoxicity biomarkers in mice. APAP-induced hepatotoxicity is characterized by hepatic centrilobular necrosis and hepatitis. APAP biotransformation by Phase I enzymes leads to the formation of the reactive metabolite N-acetyl-p-benzoquinone (NAPQI), which can deplete glutathione and form adducts with hepatic proteins (see Section 15.2). Protein adduction primes the hepatocytes for cytokines released by activated macrophages (Kupffer cells) and/or destructive insults by reactive nitrogen species. Although necrosis is recognized as the mode of cell death in APAP overdose, the precise mechanisms are still being elucidated [152]. 

Adverse reactions occur more frequently in slow acetylators. They include acute hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency, and agranulocytosis. Fever, arthralgias, and rashes occur in up to 20% of patients. Gastrointestinal complaints are common. Hypersensitivity reactions including photosensitivity are also seen. Less frequent are hepatic function disturbances. 

The most commonly observed side effects are GI disturbances and nervous system symptoms, such as nausea, vomiting, headache, dizziness, and fatigue. Hepatitis is a major adverse effect, and the risk is highest in patients with underlying liver diseases and in slow isoniazid acetylators the rate of hepatotoxicity is increased if isoniazid and rifampin are combined. 

PAS is readily absorbed from the GI tract and is widely distributed throughout body fluids except cerebrospinal fluid. It penetrates tissues and reaches high concentrations in the tuberculous cavities and caseous tissue. Peak plasma levels are reached within 1 to 2 hours of drug administration, and the drug has a half-life of about an hour. PAS is primarily metabolized by hepatic acetylation. When combined with isoniazid, PAS can function as an alternative substrate and block hepatic acetylation of isoniazid, thereby increasing free isoniazid levels. Both the acetylated and unaltered drug are rapidly excreted in the urine. The concentration of PAS in urine is high and may result in crystalluria. 

Geriatric Considerations - Summary Age is not a contraindication to INH prophylaxis or treatment of tuberculosis. Follow adult guidelines for treatment. INH maybe used in patient wit h stable hepatic disease. The risk of clinical hepatitis increases with age and has been reported in 2% of adults aged greater than 50. INH interferes with the metabolism of pyridoxine therefore concomitant pyridoxine therapy at 25mg/day is recommended to prevent neurotoxicity. INH is metabolized via acetylation in the liver. Older adults who are slow acetylators of the drug may require lower doses to achieve effective serum concentrations and prevent adverse effects. Food, especially high-fat meals, delays and reduces absorption therefore administer INH on an empty stomach. 

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