Gary P. Carlson

Potentiation of carbon tetrachloride hepatotoxicity in rats by pretreatment with polychlorinated biphenyls.

Pretreatment of male rats with Aroclor 1254 at a dose of 25 mg/kg i.p. for 6 days resulted in potentiation of the hepatotoxicity of inhaled carbon tetrachloride (CCl4) as evidenced by a decrease in liver glucose-6-phosphatase and elevations of serum glutamic oxalacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), isocitrate dehydrogenase, and sorbitol dehydrogenase. Aroclor 1254 alone did not demonstrate hepatotoxicity. Aroclor 1254 administration resulted in large increases in cytochrome c reductase, cytochrome P-450 (448) AND P-Nitroanisole demethylation. Subsequent exposure to CCl4 vapor resulted in over 70% decreases in the latter two parameters. The potentiation was dose-dependent with a dose of 5 mg/kg or higher being effective. Aroclor 1260 administration gave results similar to those of Aroclor 1254, but Aroclor 1221 enhanced CCl4 toxicity to a lesser extent.

Effect of phenobarbital and 3-methylcholanthrene pretreatment on the hepatotoxicity of 1,1,1-trichloroethane and 1,1,2-trichloroethane

Abstract Pretreatment of rats with phenobarbital potentiated the hepatotoxicity of both 1,1,1- and 1,1,2-trichloroethane given by inhalation. The toxicity of the 1,1,2-isomer was increased to a greater extent than that of the 1,1,1-isomer. 3-Methylcholanthrene pretreatment did not result in increased hepatotoxicity.

Liver enlargement and modification of hepatic microsomal drug metabolism in rats by pyrethrum

Abstract Oral administration of pyrethrum to male rats at 200 mg/kg for 23 days resulted in liver enlargement with decreases in hepatic DNA concentrations. While total lipid concentrations were increased significantly, the increases did not account for the enlargement. Protein concentrations of whole liver homogenates, 9000 g supernatants and the 105,000 g pellet were not different from controls. No significant changes occurred in hepatic water concentrations. Significant decreases in hexobarbital-induced hypnosis without concomitant changes in barbital-induced hypnosis suggested a pyrethrum-caused alteration in hepatic drug metabolism. The activities of hepatic microsomal enzymes responsible for EPN detoxification, p -nitroanisole demethylation and hexobarbital oxidation were increased to 150, 173 and 241% of control, respectively. No significant increases were noted in the demethylation of aminopyrine or oxidation of l -tryptophan. Increases in liver weight, the detoxification of EPN and demethylation of p -nitroanisole were found to be dose-related. Small increases in enzyme activities were observed at the lowest dose used of 85 mg/kg/day for 15 days. At a daily dose of 500 mg/kg/day, liver weights and enzyme activities were increased up to 17 days of treatment but returned to control level within 7 days after cessation of treatment. NADPH cytochrome c reductase activity and P-450 concentration were also increased. At high dose levels, pyrethrum will cause induction of microsomal enzymes.

The effect of polychlorinated biphenyls on adenosine triphosphatase activity

Rats treated with 25 mg/kg Aroclor 1242 ip daily for 7 days showed a significant decrease in total ATPase activity of liver, kidney, and brain tissues. In addition, a series of Aroclors produced significant in vitro inhibition of rat Mg-ATPase activity at a concentration of 30 ppm. A weak correlation was observed between increasing inhibition and increasing degree of chlorination. A rigorous evaluation of the effect of purified PCB isomers on rat ATPases showed that there was no correlation between chlorine substitution patterns and inhibitory activity. Since biphenyl, a nonchlorinated hydrocarbon, produced significant inhibition of rat ATPases, the relationship between ATPase inhibition and the lipophilic properties of PCBs was evaluated. A strong correlation between increasing PCB-induced inhibition of ATPases and decreasing aqueous solubility was observed. The data suggest that the mechanism of PCB-induced inhibition of ATPase may be the lipophilic partitioning of PCBs into the lipid fraction of the ATPase enzyme which produces an allosteric change resulting in decreased enzyme activity.

Effect of carbon monoxide or hypoxia on CCl4 hepatotoxicity

Abstract The exposure of rats to carbon monoxide concomitant with CCl4 vapor significantly enhanced the rise in SGPT and SGOT activities observed 24 hr after exposure to CCl4 vapors (4400 ppm) alone. However, exposure of rats to a hypoxic atmosphere (7.5% oxygen) with CCl4 vapor did not alter these parameters of CCl4 hepatotoxicity. Serum enzyme activity was not enhanced by exposure to carbon monoxide or hypoxia alone.

Detoxification of foreign organic compounds by the quahaug,Mercenaria mercenaria

1. The hepatopancreas of the quahaug,Mercenaria mercenaria was examined for ability to oxidize or reduce foreign organic compounds. 2. Quahaug hepatopancreas was unable to metabolize the insecticide EPN, O-demethylate p-nitroanisole, N-demethylate aminopyrine or oxidize hexobarbital. 3. Quahaug hepatopancreas was able to reduce p-nitrobenzoic acid to p-aminobenzoic acid. The reaction was maximal at 35–45°C and a pH of 6·0. It was stimulated by flavins and inhibited by potassium cyanide but not by SKF-525A or carbon monoxide. 4. Nitroreductase activity was also found in mantle, gill, foot and gonadal tissue to a lesser extent.

Effect of phenobarbital or 3-methylcholanthrene pretreatment on carbon tetrachloride-induced lipid peroxidation in rat liver☆☆☆

Abstract The enhancement of carbon tetrachloride hepatotoxicity following phenobarbital pretreatment is associated with an increase in lipid peroxidation in vivo when CCl 4 is administered orally or by inhalation. However, pretreatment with 3-methylcholanthrene did not increase in vivo lipid peroxidation following CCl 4 administration by the oral or inhalation route. CCl 4 stimulated lipid peroxidation, as determined by malonaldehyde formation in vitro , and was increased by phenobarbital pretreatment but not by 3-methylcholanthrene pretreatment. These data support a relationship between microsomal drug metabolizing activity and alterations in hepatic injury and lipid peroxidation following CCl 4 administration.

Protection against carbon tetrachloride-induced hepatotoxicity by pretreatment with methylmercury hydroxide.

Pretreatment of rats with methylmercury hydroxide (MMH) (15 mg/kg s.c. for 2 days) protected against hepatotoxicity due to the inhalation of CCl4 vapor (4800-6100 ppm for 2 h). This was evidenced by lessening of the changes due to CCl4 in liver glucose-6-phosphatase, serum glutamic oxalacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), serum isocitrate dehydrogenase and serum sorbitol dehydrogenase. Decreases in p-nitroanisole demethylation and cytochrome P-450 were also altered. Lipid peroxidation due to CCl4 was decreased by MMH. These biochemical indices of protection were supported by histopathological observations. These results lend further support to the concept that metabolism of CCl4 is necessary for its hepatoxicity.

Relationship between sulfhydryl reactivity and toxicity of vinyl sulfone molluscicidal agents

Abstract Vinyl sulfone was tested to determine (a) sulfhydryl reactivity, ascertained by monitoring the color-forming reaction between 5,5′-dithiobis(2-nitrobenzoic acid) and cysteine, (b) inhibition of malic dehydrogenase, (c) inhibition of in vitro endogenous respiration in the snail Australorbis glabratus , (d) the in vitro effect on endogenous respiration and pyruvate metabolism of liver and brain of albino rats, and (e) pyruvate metabolism in liver, kidney, and brain homogenates of male rats treated in vivo with vinyl sulfone. The effects of sublethal doses of vinyl sulfone on albino rats were also investigated. A series of vinyl sulfone molluscicidal agents was shown to exhibit a positive correlation between sulfhydryl reactivity and molluscicidal potency. High concentrations (>2 m m ) of vinyl sulfone were required to inhibit the activity of malic dehydrogenase. No effect on endogenous respiration was observed in snails. Similarly, no effects on endogenous respiration or pyruvate metabolism was observed in rats. An ip LD50 of 3 mg/kg vinyl sulfone was found in female rats. A sublethal dose of vinyl sulfone increased blood urea nitrogen and decreased urinary output while producing no effect on SGOT and SGPT activity or on hematocrit values in rats. These data indicate that the toxicity of vinyl sulfone is not related to the inhibition of endogenous respiration in either snails or rats. The toxicity of sublethal doses of vinyl sulfone was postulated to be caused by impairment of normal renal function.

Azoreductase activity in the hard clam, Mercenaria mercenaria (L.)

Abstract The ability of the hard clam Mercenaria mercenaria (L.) to metabolize compounds containing an azo linkage has been investigated. The hepatopancreas has azoreductase activity as evidenced by the reduction of 1,2-dimethyl-4-(p-carboxyphenylazo)-5-hydroxybenzene. This activity was higher at 37°C than at 22°C and the pH optimum was 8.0. The reaction was stimulated by the addition of flavin mononucleotide and inhibited by air. Activity was found in both the 105,000 g soluble and the microsomal fractions of the hepatopancreas.