Acetylation genetic factors

There are examples where several genetic factors, including the acetylator phenotype, operate together. Hydralazine toxicity is one such example, which is discussed in detail in chapter 7. Another is the hemolytic anemia caused by the drug thiozalsulfone (Promizole), which occurs particularly in those individuals who are both glucose-6-phosphate dehydrogenase deficient and slow acetylators. Promizole is acetylated, and studies in rapid and slow acetylator mice confirmed that acetylation was a factor as well as an extent of hydroxylation. The latter may also be another factor in humans as is discussed below. 

Genetic factors are particularly important in humans and can influence the response to the compound or the disposition of the compound and hence its toxicity. Several genetic factors affecting metabolism are known in which a nonfunctional, less functional, or unstable form of the enzyme is produced in a particular phenotype, for example, acetylator phenotype... 

Genetic factors that influence enzyme levels account for some of these differences. Succinylcholine, for example, is metabolized only half as rapidly in persons with genetically determined defects in pseudocholinesterase as in persons with normally functioning pseudocholinesterase. Analogous pharmacogenetic differences are seen in the acetylation of isoniazid (Figure 4-5) and the hydroxylation of warfarin. The defect in slow acetylators (of isoniazid and similar amines) appears to be caused by the synthesis of less of the enzyme rather than of an abnormal form of it. Inherited as an autosomal recessive trait, the slow acetylator phenotype occurs in about 50% of blacks and... 

Genetic factors account for some ADRs due to either altered pharmacokinetics or by altering tissue responsiveness. Altered metabolism of drugs occurs due to differences in hydrolysis, acetylation, and hepatic oxidation of drugs. Altered pharmacodynamic reactions could be either an exaggerated response or a... 

Acetylator status and other genetic factors, old age, preexisting hepatic dysfunction, alcoholism, co-infection with hepatitis virus, and malnutrition are important potential susceptibility factors for the development of liver damage in patients taking antituberculosis drugs (21), but there have been inconsistent findings with regard to some of these risk factors in different studies. 

The acetylation of isoniazid and acetylhydrazine are both subject to genetic variability, so the production and detoxication pathways are both influenced by the acetylator phenotype. The hepatotoxicity of isoniazid is therefore dependent on a complex interrelationship between genetic factors and individual variation in the pharmacokinetics of isoniazid. Studies of the pharmacokinetics of acetylhydrazine in human subjects after a dose of isoniazid have revealed that although the peak plasma concentration of acetylhydrazine is higher in rapid acetylators, when the plasma concentration of acetylhydrazine is plotted against time, the area under the curve... 

Isoniazid causes peripheral neuropathy and liver damage (centrilobular necrosis). The liver damage is caused by a metabolite, acetylhydrazine whereas the peripheral neuropathy is caused by the parent drug interacting with pyridoxal phosphate and thereby interfering with the metabolism of vitamin B6. The genetic factor acetylator phenotype is important in both types of toxicity. Thus... 

A study found that aminosalicylic acid significantly increased the plasma levels of isoniazid at 4 and 6 hours after administration by 32% and 114%, respectively in fast acetylators of isoniazid, and by 21% and 39%, respectively in slow acetylators. The half-life of isoniazid was increased from 1.32 to 2.89 hours in fast acetylators and from 3.05 to 4.27 hours in slow acetylators (see Genetic factors , (p.4), for more information about acetylator status). The effects were probably due to the inhibition of isoniazid metabolism by aminosalicylic acid. There seem to be no reports of isoniazid toxicity arising from this interaction, but the manufacturers of isoniazid warn that adverse effects are more likely in the presence of aminosalicylic acid. ... 

Rifabutin 300 mg, given daily for 7 days to 6 healthy subjeets, had no significant effect on the pharmacokinetics of a single 300-mg dose of isoniazid or its metabolite acetylisoniazid. Two of the 6 subjects were rapid acetylators of isoniazid (see Genetic factors , (p.4), for more information about acetylator status). 

Although genetic variation in many genes may be associated with differential drug responses, it is also apparent that other factors, such as epigenetics (DNA methylation, interference RNA, RNA editing, histone acetylation/deacetylation. 

It is also clear that apart from exposure to carcinogens, other factors such as the genetic predisposition of the organism exposed may also be important. Thus, patients with the genetic disease xeroderma pigmentosum are more susceptible to skin cancer. It has already been mentioned that the incidence of bladder cancer is significantly higher in those individuals who have the slow acetylator phenotype. 

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