Hepatic enzymes aminotransferases

Toxicities are GI (stomatitis, diarrhea, nausea, vomiting), hematologic (thrombocytopenia, leukopenia), pulmonary (fibrosis, pneumonitis), and hepatic (elevated enzymes, rare cirrhosis). Concomitant folic acid may reduce some adverse effects without loss of efficacy. Liver injury tests (aspartate aminotransferase or alanine aminotransferase) should be monitored periodically, but a liver biopsy is recommended during therapy only in patients with persistently elevated hepatic enzymes. MTX is teratogenic, and patients should use contraception and discontinue the drug if conception is planned. 

Use of zileuton is limited due to the potential for elevated hepatic enzymes (especially in the first 3 months of therapy), and inhibition of the metabolism of some drugs metabolized by CYP3A4 (e.g., theophylline, warfarin). Serum alanine aminotransferase should be monitored before treatment and then periodically thereafter. 

Hepatic Effects. Enlarged liver and elevated serum levels of hepatic enzymes indicative of liver injury (lactate dehydrogenase, 2 times above normal aspartate aminotransferase, 21 times above normal alanine aminotransferase, 100 times above normal) were observed in an individual following chronic daily exposure to vapors and spills of phenol (Merliss 1972). The symptoms lessened when the... 

Hepatic Effects. Carbon tetrachloride has been known for many years to be a powerful hepatotoxic agent in humans and in animals. The principal clinical signs of liver injury in humans who inhale carbon tetrachloride are a swollen and tender liver, elevated levels of hepatic enzyme (aspartate aminotransferase) in the serum, elevated serum bilirubin levels and the appearance of jaundice, and decreased serum levels of proteins such as albumin and fibrinogen (Ashe and Sailer 1942 McGuire 1932 New et al. 1962 Norwood et al. 1950 Straus 1954). In cases of acute lethal exposures, autopsy generally reveals marked liver necrosis with pronounced steatosis (Jennings 1955 Markham 1967 Smetana 1939), and repeated or chronic exposures leads in some cases to fibrosis or cirrhosis (McDermott and Hardy 1963). 

Dayal et al. (1989) treated BALB/c mice intraperitoneally with a single dose of 9 mmol/kg bw 2-nitropropane. In male mice, plasma activities of the hepatic enzymes sorbitol dehydrogenase, alanine aminotransferase and aspartate aminotransferase were significantly elevated, while doses of 6.7 mmol/kg bw were ineffective. In female mice, a dose of 6.7 mmol/kg bw was sufficient to cause hepatotoxicity. Histopathological evaluation revealed hepatic damage, particularly in the periportal region. 

In recent studies(23,26) attempts were made to normalize the tumor-induced abnormalities in the levels of hepatic enzymes. It is known that catalysts of the urea cycle are induced by high protein diet, while high carbohydrate intake, decreasing the levels of alanine aminotransferase, increases those of malic enzyme and pyruvate kinase. In each case, the same percent change was seen in tumor-bearing and normal adult animals (Table V), so that the tumor-induced defiency of such enzymes seen in rats on a normal diet was also apparent on these altered diets. Hormone treatments,... 

It has been noted in the case of several enzymes that their artificial prococious induction is reversible in that, unless the injection of the appropriate hormone is repeated, the enzyme disappears again. Why is it then that after its natural appearance at the scheduled time, the persistence of the enzyme does not hinge on the continued action of that hormone For example, glucocorticoid is undoubtedly the essential developmental stimulus for the hepatic ornithine aminotransferase(14), a member of the late suckling cluster. Its normal emergence on day 12 can be prevented by prior adrenalectomy, its precocious synthesis (5-10 days before schedule) can be evoked by an injection of cortisol, and yet no loss at all is incurred by adrenalectomy performed at or after the time at which ornithine aminotransferase has attained near adult or adult values (i.e. on day 20 or later). 

Fig. 25.7. The development of alcohol-induced hepatitis. (1) Acetaldehyde adduct formation decreases protein synthesis and impairs protein secretion. (2) Free radical injury results partly from acetaldehyde adduct formation with glutathione. (3) Induction of MEOS increases formation of free radicals, which leads to Upid peroxidation and cell damage. (4) Mitochondrial damage inhibits the electron transport chain, which decreases acetaldehyde oxidation. (5) Microtubule damage increases VLDL and protein accumulation. (6) CeU damage leads to release of the hepatic enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST).

Elevated levels of certain hepatic enzymes [e.g., aspartate aminotransferase (AST), lactate dehydrogenase (LDH), sorbitol dehydrogenase (SDH), arxl arginase] indicate hepatic necrosis [see Chapter 8 III C 2 a (4) (b). Table 8-1)]. Serum or plasma liver enzymes may be elet ed 3-6 weeks before a hemolytic crisis and may be used to prerict animals at risk. 

Ornithine aminotransferase (EC 2.6.1.13) Ubiquitous" Mitochondrial matrix Hepatic enzyme induced by dietary protein, glucagon kidney enzyme induced by estrogens. Increased in mammary tissue with lactogenesis... 

Use of the plasma enzyme alanine aminotransferase (ALT) in monitoring the progress of infectious hepatitis. 

Hepatic Effects. Two days after a man was splashed with a phenol-water solution over his face, chest wall, hand, and both arms, serum bilirubin increased 2-fold (Horch et al. 1994). After 5 days, serum bilirubin returned to normal. An enlarged and tender liver and increased liver enzymes in the serum were reported in a case of chronic phenol poisoning (Merliss 1972). Lactate dehydrogenase was about 2-fold greater than normal, aspartate aminotransferase was about 21-fold greater than normal, and alanine aminotransferase was about 100-fold greater than normal. The man worked in a laboratory for 13.5 years where he distilled phenol several times a day. During the process, heavy odors were detectable, phenol was often spilled on his clothes, and he noted skin irritation. 

Hepatomegaly, jaundice, and altered liver function tests have been reported in accidental poisonings with DME An outbreak of toxic liver disease was associated with DME exposure at a fabric coating factory. Thirty-six of 58 workers had elevations of either aspartate aminotransferase or alanine aminotransferase. Serological tests excluded known infectious causes of hepatitis in all but two cases. After modification of work practices and removal of the most severely affected from exposure, improvement in liver enzyme abnormalities and symptoms occurred in most patients. Medical surveillance of the working population for 14 months revealed no further cases of toxic liver... 

Hepatic Effects. An animal study revealed that hexachlorobutadiene can affect the liver. However, the effects were less serious compared to effects in the kidney at the same dose. Liver weights were decreased in female rats fed 5 mg/kg/day or greater hexachlorobutadiene for 4 weeks (Jonker et al. 1993b). Histological examinations were not performed. However, evaluation of serum biochemical parameters in males revealed increased enzyme activity (aspartate aminotransferase, p <0.02) and total bilirubin levels (p<0.02) at doses of 20 mg/kg/day (highest dose tested). 

Hepatic Effects. Liver injury, characterized by an elevated serum enzyme (alanine aminotransferase level), was described in case reports of three humans after dermal application of carbon tetrachloride (Perez et al. 1987). In the absence of quantitative estimates of the amount of carbon tetrachloride applied or absorbed, NOAEL and LOAEL values cannot be determined. 

E. Therapeutic response A randomized trial compared treatment with PEG-Intron, once weekly, to treatment with Intron A (interferon alfa-2b), three times weekly, in 1219 previously untreated adults with chronic hepatitis from HCV infection. Patients were treated for 48 weeks. Response to treatment was defined as undetectable HCV RNA (less than 100 copies per ml) and normalization of the liver enzyme alanine aminotransferase (ALT) at 24 weeks post-treatment. Response rates to the l.Opg/kg PEG-Intron doses and to Intron A were 24% and 12%. Patients receiving PEG-Intron with viral genotype 1 had a response rate of 14%, while patients with other viral genotypes had a 45% response rate. 

Some cases of hepatotoxicity have been reported to be associated with exposure to coumarin. One possible case was reported by Beinssen (1994) and six by Loprinzi et al. (1997). Marshall et al. (1994) reported one case in which elevated serum aminotransferase levels were measured in a patient given 5 g coumarin per day. In two lymphoedema patients given 90 mg coumarin per day for five months, Koch et al. (1997) reported elevated serum alanine aminotransferase activity. Faurschou (1982) reported a case of toxic hepatitis in a patient given coumarin daily for eight weeks, which was characterized by hepatomegaly and elevated serum enzyme levels. All signs of liver toxicity returned to normal on cessation of treatment. 

Some enzymes show relatively high activity in only one or a few tissues. The presence of increased levels of these enzymes in plasma thus reflects damage to the corresponding tissue. For example, the enzyme alanine aminotransferase ALT, see p. 248) is abundant in the liver. The appearance of elevated levels of ALTin plasma signals possible damage to hepatic tissue. Increases in plasma levels of enzymes with a wide tissue distribution provide a less specific indication of the site of cellular injury. This lack of tissue specificity limits the diagnostic value of many plasma enzymes. 

Both aspartate aminotransferase and alanine aminotransferase are released into the blood after damage to tissues or after cell death. Consequently, they are used as diagnostic tools when heart or liver damage has occurred, such as after a heart attack or in hepatitis, respectively. Other enzymes are also released into the blood at such times. For example, damage to heart muscle is further characterized by the presence of isoenzymes of creatine kinase or lactate dehydrogenase in the plasma. 

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