Carbon tetrachloride, enzyme

Trichloroethylene may occur in drinking water along with other chlorinated hydrocarbons, so effects of these chemicals in combination are of interest to public health. Hepatotoxicity, as measured by plasma enzyme activity, was increased synergistically in rats by oral administration of carbon tetrachloride combined with trichloroethylene (Borzelleca et al. 1990). In addition, synergistic effects were implicated in a 3-day study in... 

This rule holds reasonably well when C or t varies within a narrow range for acute exposure to a gaseous compound (Rinehart and Hatch, 1964) and for chronic exposure to an inert particle (Henderson et al., 1991). Excursion of C or / beyond these limits will cause the assumption Ct = K to be incorrect (Adams et al., 1950, 1952 Sidorenko and Pinigin, 1976 Andersen et al., 1979 Uemitsu et al., 1985). For example, an animal may be exposed to 1000 ppm of diethyl ether for 420 min or 1400 ppm for 300 min without incurring any anesthesia. However, exposure to 420,000 ppm for lmin will surely cause anesthesia or even death of the animal. Furthermore, toxicokinetic study of fiver enzymes affected by inhalation of carbon tetrachloride (Uemitsu et al., 1985), which has a saturable metabolism in rats, showed that Ct = K does not correctly reflect the toxicity value of this compound. Therefore, the limitations of Haber s rule must be recognized when it is used in interpolation or extrapolation of inhalation toxicity data. 

Rao SB, Young RA, Mehendale HM. 1989. Hepatic polyamines and related enzymes following chlordecone-potentiated carbon tetrachloride toxicity in rats. J Biochem Toxicol 4(1) 55-63. 

In animal studies acetone has been found to potentiate the toxicity of other solvents by altering their metabolism through induction of microsomal enzymes, particularly cytochrome P-450. Reported effects include enhancement of the ethanol-induced loss of righting reflex in mice by reduction of the elimination rate of ethanol increased hepatotoxicity of compounds such as carbon tetrachloride and trichloroethylene in the rat potentiation of acrylonitrile toxicity by altering the rate at which it is metabolized to cyanide and potentiation of the neurotoxicity of -hexane by altering the toxicokinetics of its 2,4-hexane-dione metabolite.Because occupationally exposed workers are most often exposed to a mixmre of solvents, use of the rule of additivity may underestimate the effect of combined exposures. ... 

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). 

In animals, the hepatic effects of inhalation exposure to carbon tetrachloride are much the same as in humans elevated serum enzyme levels, steatosis and centrilobular necrosis progressing to fibrosis. In rats, exposure to concentrations of 10-100 ppm are generally observed to result in mild to moderate signs of liver injury, both after short-term and intermediate exposure (Adams et al. 

The hepatotoxic effects of carbon tetrachloride have been widely studied in animals. Indeed, carbon tetrachloride is used as a model chemical in many laboratory investigations of the basic mechanism of action of hepatotoxic chemicals. Oral exposure to carbon tetrachloride has been observed to result in a wide spectrum of adverse effects on the liver, the most prominent of which are destruction of the smooth and rough endoplasmic reticulum and its associated enzyme activities (Reynolds and Yee 1968), inhibition of protein synthesis (Lutz and Shires 1978), impaired secretion of triglycerides with resultant fat accumulation (Fischer-Nielsen et al. 1991 Recknagel and Ghoshal 1966 Recknagel and Glende 1973 Waterfield et al. 1991), centrilobular necrosis (Blair et al. 1991 Reynolds and Yee 1968 Waterfield et al. 1991 Waterfield et al. 1991 Weber et al. 1992), and eventually fibrosis and cirrhosis (Allis et al. 1990 Bruckner et al. 1986 Fischer-Nielsen et al. 1991 Weber etal. 1992). 

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. 

Cytochrome P-450 from rat or human liver microsome preparations is inactivated when incubated anaerobically with carbon tetrachloride in the presence of NADPH and an oxygen-scavenging system (Manno et al. 1988 1992). Inactivation involved destruction of the heme tetrapyrrolic structure, and followed pseudo first-order kinetics with fast and slow half lives of 4.0 and 29.8 minutes. When compared with rat liver microsomes, the human preparations were 6-7 times faster at metabolizing carbon tetrachloride, and only about one- eighth as susceptible to suicide inactivation (about 1 enzyme molecule lost for every 196 carbon tetrachloride molecules metabolized). 

Hepatic Effects. Human and animals studies of carbon tetrachloride toxicity reveal that the principal adverse systemic effect in injury to the liver, as evidenced by clinical signs jaundice, swollen and tender liver), biochemical alterations (elevated levels of hepatic enzymes in the blood, loss of... 

Detection of liver injury has commonly been associated with alternations in serum levels of certain hepatic enzymes and proteins. Elevation in bilirubin levels following exposure (Barnes and Jones 1967) has been detected in humans, as have decreased serum levels of secreted liver proteins (e.g., albumin and fibrinogen) (Ashe and Sailer 1942 McGuire 1932 New et al. 1962 Norwood et al. 1950 Straus 1954). Elevations in serum levels of enzymes (e.g., ALT, AST, LDFI, OCT) have been reported following acute- and intermediate-duration exposures to carbon tetrachloride in animals (Bruckner et al. 1986 FI ayes et al. 1986 Sakata et al. 1987). 

Basis for differences in carbon tetrachloride effects on periportal and pericentral hepatocytes enzymic and metabolic variations. 

Cheadwick RW, Copeland MF, Carlson GP, et al. 1988. Comparison of in vitro methods for assessing the effects of carbon tetrachloride on the hepatic drug-metabolizing enzyme system. Toxicol Lett 42 309-316. 

Korsrud GO, Grice HC, McLaughlan JM. 1972. Sensitivity of several serum enzymes in detecting carbon tetrachloride-induced liver damage in rats. Toxicol AppI Pharmacol 22 474-483. 

Lloyd SA, Franklin MR. 1991. Modulation of carbon tetrachloride hepatoxicity and xenobiotic-metabolizing enzymes by corticosterone pretreatment, adrenalectomy and sham surgery. Toxicol Lett 55 65- 75. 

Matkovics B, Novak R, Szabo L, et al. 1978. Effect of acute carbon tetrachloride intoxication on the lipid peroxidation and the enzymes of the perioxide metabolism of rat tissues. Gen Pharmacol... 

McLean AEM, McLean EK. 1966. The effect of diet and 1,1,1-trichloro-2,2-bis-(p-chlorophenyl)ethane (DDT) on microsomal hydroxylating enzymes and on sensitivity of rats to carbon tetrachloride poisoning. Biochem J 100 564- 571. 

Murphy SD, Malley S. 1969. Effect of carbon tetrachloride on induction of liver enzymes by acute stress or corticosterone. Toxicol AppI Pharmacol 15 117-130. 

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