Serum Ornithine Carbamyl Transferase Activity Research Articles

Retrospective evaluation of serum ornithine carbamyltransferase activity as an index of hepatotoxicity in toxicological studies with rats

The sensitivity of elevated serum ornithine carbamyltransferase (OCT) as an index of hepatotoxicity in rats was assessed in different studies conducted over a number of years and originally designed to examine the toxicity or carcinogenicity of a variety of test chemicals and diets. Changes in serum OCT activities were compared with the more widely used clinical endpoints, alanine aminotranserase (ALT) and aspartate aminotransferase (AST). In the first study, rats received a single oral dose of the hepatotoxic and hepatocarcinogenic fungal toxin aflatoxin B 1 (AFB 1). The increase in enzyme levels between control and AFB 1-treated rats was greater for serum OCT than for ALT or AST. This response was similar to the changes in serum enzyme levels in studies where rats ingested a hepatotoxic and hepatocarcinogenic choline deficient (CD) diet. When rats were exposed to the hepatotoxic and nephrotoxic fungal toxin fumonisin B 1 (FB 1) by intraperitoneal injection for 6 days, serum AST and ALT were significantly elevated above control levels while OCT was unaffected. The peroxisome proliferator ciprofibrate caused elevated ALT and AST but not OCT at week 52 of dietary exposure, after the development of liver nodules and tumours. Of the two liver-specific enzymes examined in all of the studies, ALT was more consistently predictive of hepatotoxicity than OCT.

Formation of Paramagnetic Chromium in Liver of Mice Treated with Dichromate (VI)

The formation of paramagnetic chromium in the liver of male mice dosed with K2Cr2O7 (10, 20, and 40 mg Cr/kg) by a single ip injection was investigated by electron spin resonance (ESR) spectrometry. Both Cr(V) and Cr(III) complexes were detected in the mice livers at 15 min to 12 hr after Cr(VI) injection. The time course (15 min-12 hr) for the formation of paramagnetic Cr revealed that the hepatic levels of Cr(V) complexes decreased quickly during the first hour but decreased more slowly over the next 11 hr. However, in contrast to Cr(V), Cr(III) complexes appeared to persist for 12 hr after Cr(VI) treatment based on figures of Cr(III) signal. Thus, Cr(III) may be the ultimate form following reduction of Cr(VI) in liver. The total Cr content in liver of mice dosed with dichromate was also increased in a dose-dependent fashion (10-40 mg Cr/kg). However, Cr content in liver remained at similar levels for 15 min-6 hr, and slightly decreased at 12 hr after Cr(VI) injection. Under the same experimental conditions, hepatotoxicity, as estimated by the increase of serum ornithine carbamyl transferase activity, appeared at 3 hr after 20 and 40 mg Cr/kg of Cr(VI) injection, while 10 mg Cr/kg of Cr(VI) produced no hepatotoxicity even at 12 hr. Predosing with phenobarbital, which increased the hepatic levels of cytochrome P450, resulted in a decrease of the levels of Cr(V) and in a small increase of Cr content, without affecting Cr(VI) hepatotoxicity. On the other hand, pretreatment with buthionine sulfoximine, which depleted hepatic glutathione (GSH) levels, caused a decrease of Cr(VI) hepatotoxicity, but the levels of Cr(V) and Cr in the liver remained unchanged. These results demonstrated that in vivo formation of paramagnetic Cr, in particular Cr(V), in liver of mice is clearly detected and quantified by ESR spectrometry and that hepatic levels of cytochrome P450 and GSH are associated with the induction of biological effects by Cr(VI) in liver in vivo. The results also suggested that the formation of Cr(V) was not the only mechanism involved in the induction of hepatotoxicity by Cr(VI) compounds.

Role of cytochrome P450 in hepatotoxicity induced by di- and tributyltin compounds in mice.

The role of cytochrome P450 in the induction of hepatotoxicity by butyltin compounds such as tributyltin chloride (TBTC) and dibutyltin dichloride (DBTC) was investigated in vivo. The pretreatment of mice with SKF-525A, which decreased hepatic levels of cytochrome P450, suppressed TBTC-induced hepatotoxicity, as estimated by serum ornithine carbamyl transferase activity, whereas pretreatment with phenobarbital (PB), which increased the levels of cytochrome P450, enhanced the hepatotoxicity of TBTC. In the case of DBTC, PB pretreatment enhanced hepatotoxicity, while SKF-525A had no effect. Under these experimental conditions only PB pretreatment was found to increase hepatic levels of tin in mice treated with TBTC. These results suggest that hepatic metabolism of butyltin compounds by cytochrome P450 is more closely related to the induction of hepatotoxicity by TBTC than by DBTC. The active tin compounds formed during hepatic metabolism, which are responsible for induction of hepatotoxicity, will be discussed.

Oral toxicity of 1,2-dichloropropane: Acute, short-term, and long-term studies in rats

The objective of this investigation was to characterize the acute and short- and long-term toxic potency of orally administered 1,2-dichloropropane (DCP). In the acute and short-term studies, male rats of 250–300 g were gavaged with 0, 100, 250, 500, or 1000 mg DCP/kg in corn oil once daily for up to 10 consecutive days. Although ingestion of DCP caused body weight loss and CNS depression, few other toxic effects were manifest 24 hr after a single dose of the chemical. Morphological changes were limited to liver centrilobular cells in 500 and 1000 mg/kg rats. Similarly, elevated activity of some serum enzymes occurred only at these two highest dose levels. Hepatic nonprotein sulfhydryl (NPS) levels were decreased and renal NPS levels increased at 24 hr. In the short-term study resistance developed to DCP hepatotoxicity over the 10 consecutive days of exposure, as reflected by progressively lower serum enzyme levels and by decreases in the severity and incidence of toxic hepatitis and periportal vacuolization. Nucleolar enlargement in hepatocytes, however, was observed at all dosage levels at 5 and 10 days. There were a number of manifestations of hemolytic anemia, including erythrophagocytosis in the liver, splenic hemosiderosis and hyperplasia of erythropoietic elements of the red pulp, renal tubular cell hemosiderosis, and hyperbilirubinemia. Urinalyses and histopathology revealed no evidence of nephrotoxicity. In the long-term study, male rats initially weighing 180–200 g were gavaged five times weekly for up to 13 weeks with 0, 100, 250, 500, or 750 mg DCP/kg. As over one-half the 750 mg/kg group died within 10 days, the survivors were sacrificed. Histopathological changes in the 750 mg/kg animals included mild hepatitis and splenic hemosiderosis, as well as adrenal medullary vacuolization and cortical lipidosis, testicular degeneration and a reduction in sperm, and increased number of degenerate spermatogonia in the epididymis in some members of the group. Similar testicular and epididymal degenerative changes also were observed in some 500 mg/kg animals after 13 weeks of dosing. There was a progressive increase in the number of deaths in the 500 mg/kg group, such that more than 50% were dead by 13 weeks. No deaths occurred in the 100 or 250 mg/kg groups. The DCP dosage regimen also produced a dose-dependent decrease in body weight gain. DCP exhibited very limited hepatotoxic potential and no apparent nephrotoxic potential in the long-term study. Slight elevations in serum ornithine-carbamyl transferase activity, periportal vacuolization, and active fibroplasia in the liver were seen in the 500 mg/kg animals. Dose-dependent elevations in serum bilirubin were measured at most time points, and at 10 and 12 weeks the increases were sufficient to be statistically significant in the 100 mg/kg group. Hemosiderosis and hyperplasia of erythropoietic elements of the spleen were present in most DCP-dosed animals at all exposure levels. Liver/body weight and spleen/body weight ratios were higher, while hematocrit and hemoglobin levels were significantly lower, than those of controls in the 250 and 500 mg/kg animals. These effectsof the long-term dosage regimen largely disappeared during a 1-week recovery period.

Ornithine carbamyl transferase in Reye's syndrome

Serum levels of ornithine carbamyl transferase activities were determined in the acutely ill and convalescent Reye's syndrome patients and in their parents. Acutely ill Reye's syndrome patients had elevated levels of serum ornithine carbamyl transferase activities as compared to those in controls. The convalescent Reye's syndrome patients and their parents had normal levels of serum ornithine carbamyl transferase activities. These results suggest that an inborn metabolic defect was not responsible for the increase in serum ornithine carbamyl transferase activities in Reye's syndrome.

MASKING BY ENZYME INHIBITOR OF RAISED SERUM GLUTAMATE DEHYDROGENASE ACTIVITY IN REYE'S SYNDROME

Serum glutamate dehydrogenase (GDH) activity was greatly raised (up to 830 times the upper limit of normal) in 16 patients with Reye's syndrome. The serum activity was masked by an inhibitor, and the rises were observed only after dialysis or sample dilution. Serum GDH values from 38 paediatric patients, including 10 with hyperammonaemia due to other causes, showed no such rise after dialysis. Only 1 of 13 adult patients with liver disease had high GDH activity, but this level was not increased after dialysis. Serum ornithine carbamyl transferase activity was also raised in patients with Reye's syndrome, but levels were not increased after dialysis. The ratio of dialysed/undialysed GDH activity clearly distinguished all Reye's patients from controls. The inhibition of a mitochondrial enzyme which regulates ammonia metabolism may contribute to the hyperammonaemia of Reye's syndrome. Serum GDH levels before and after dialysis would seem to be a useful diagnostic aid in Reye's disease.

Increased Carbon Tetrachloride Hepatotoxicity, and its Mechanism, After Chronic Ethanol Consumption

Clinical observations suggest that alcoholism predisposes to CCl4 hepatotoxicity. To study whether hepatic changes secondary to chronic ethanol consumption play a role, female rats were pair-fed, for 4 to 5 weeks, a nutritionally adequate liquid diet containing either ethanol (36% of total calories) or isocaloric carbohydrate (controls). CCl4 (0.5 ml per kg) was given intragastrically 15 hr after ethanol withdrawal. Within 24 hr, serum ornithine carbamyl transferase activity as well as liver lipid increased, whereas hepatic cytochrome P-450 content and the activities of hepatic aminopyrine N-demethylase and glucose-6-phosphatase decreased. All of these CCl4-induced changes were significantly greater in rats fed ethanol chronically than in their pair-fed controls. Moreover, in the ethanol-CCl4 treated animals, the activities of serum ornithine carbamyl transferase and glutamic pyruvic transaminase, and the concentration of serum bilirubin and liver lipid were significantly higher, whereas the content of hepatic cytochrome P-450, as well as the activities of hepatic aminopyrine N-demethylase and of glucose-6-phosphatase, were significantly lower than the values obtained in rats treated with CCl4 alone. These findings indicate the in vivo potentiation of CCl4 hepatotoxicity by chronic ethanol consumption, even in the absence of ethanol at the time of CCl4 administration. To study the mechanism of this ethanol-CCl4 synergism, liver microsomes were incubated with CCl4 and a reduced nicotinamide adenine dinucleotide phosphate-generating system. Destruction of cytochrome P-450 in vitro caused by CCl4 was much greater in microsomes of ethanol-treated rats than in their controls. In addition, chronic ethanol consumption increased the covalent binding of 14CCl4 metabolites to microsomal protein in vitro. Furthermore, the metabolism of 14CCl4 to 14CO2 in vitro was also found to be enhanced in the ethanol-fed rats. These results suggest that the increase of the CCl4 hepatotoxicity in chronic ethanol-fed rats is due to an enhanced microsomal activation and biotransformation of CCl4.

Serum ornithine carbamyl transferase as a liver response test for exposure to organic solvents.

Ornithine carbamyl transferase (OCT), an enzyme found predominantly in the liver, is released into the bloodstream when liver cells are ruptured. The measurement of serum OCT activity is a convenient, specific, and sensitive assay of liver damage. This test was used to evaluate the effect of several widely used solvents on the livers of guinea pigs. Each solvent was administered intraperitoneally, and 24 hours later serum OCT activity was measured. Many of the solvents tested failed to increase serum OCT activity even at near-lethal doses. Of the thirty-three solvents evaluated, two produced elevations in serum OCT activity at relatively low doses (less than 50 mg/kg), five at moderate doses (50 to 500 mg/kg), and nine at high doses (greater than 500 mg/kg).

Serum ornithine carbamyl transferase activity in sheep and cattle

Two procedures for the measurement of ornithine carbamyl transferase activity in bovine and ovine sera are compared and the sensitivity of estimation of serum OCT activity in detection of hepatic cell necrosis is compared with that of estimation of serum glutamic oxalacetic transaminase activity.

Serum ornithine carbamyl transferase activity in normal pregnancy and in pregnancy complicated by pruritus.

Acta Obstetricia et Gynecologica ScandinavicaVolume 40, Issue 3 p. 244-251 Serum Ornithine Carbamyl Transferase Activity in Normal Pregnancy and in Pregnancy Complicated by Pruritus Hans Reichard, Hans Reichard King Gustaf V Research Institute, Stockholm, Sweden Department of Internal Medicine, National Institute of Public Health, Stockholm, Sweden Department of Women's Diseases, Karolinska Sjukhuset, Stockholm, Sweden National Institute of Public Health, Department of Industrial Health, Stockholm, SwedenSearch for more papers by this authorNils Wiqvist, Nils Wiqvist King Gustaf V Research Institute, Stockholm, Sweden Department of Internal Medicine, National Institute of Public Health, Stockholm, Sweden Department of Women's Diseases, Karolinska Sjukhuset, Stockholm, Sweden National Institute of Public Health, Department of Industrial Health, Stockholm, SwedenSearch for more papers by this authorSven Yllner, Sven Yllner King Gustaf V Research Institute, Stockholm, Sweden Department of Internal Medicine, National Institute of Public Health, Stockholm, Sweden Department of Women's Diseases, Karolinska Sjukhuset, Stockholm, Sweden National Institute of Public Health, Department of Industrial Health, Stockholm, SwedenSearch for more papers by this author Hans Reichard, Hans Reichard King Gustaf V Research Institute, Stockholm, Sweden Department of Internal Medicine, National Institute of Public Health, Stockholm, Sweden Department of Women's Diseases, Karolinska Sjukhuset, Stockholm, Sweden National Institute of Public Health, Department of Industrial Health, Stockholm, SwedenSearch for more papers by this authorNils Wiqvist, Nils Wiqvist King Gustaf V Research Institute, Stockholm, Sweden Department of Internal Medicine, National Institute of Public Health, Stockholm, Sweden Department of Women's Diseases, Karolinska Sjukhuset, Stockholm, Sweden National Institute of Public Health, Department of Industrial Health, Stockholm, SwedenSearch for more papers by this authorSven Yllner, Sven Yllner King Gustaf V Research Institute, Stockholm, Sweden Department of Internal Medicine, National Institute of Public Health, Stockholm, Sweden Department of Women's Diseases, Karolinska Sjukhuset, Stockholm, Sweden National Institute of Public Health, Department of Industrial Health, Stockholm, SwedenSearch for more papers by this author First published: January 1961 https://doi.org/10.3109/00016346109160064Citations: 2AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume40, Issue3January 1961Pages 244-251 RelatedInformation