Robert C. James

Polychlorinated biphenyl exposure and human disease.

Polychlorinated biphenyls (PCBs) continue to be of great environmental and occupational health interest. This review summarizes the major clinical findings reported in individuals incurring the greatest PCB exposure--those persons working in the manufacture or repair of electrical capacitors or transformers. The potential target organs addressed in the studies reviewed include the liver, lungs, skin, cardiovascular system, nervous system, certain endocrine systems, the blood/immune system, and the gastrointestinal and urinary tracts. After careful analysis, the weight of evidence suggests the only adverse health effects attributable to high, occupational PCB exposures are dermal. This review confirms and extends the observations of others, ie, that the collective occupational experience with PCB fluids provides no evidence for adverse PCB effects on any other organ systems.

An assay for cocaethylene and other cocaine metabolites in liver using high-performance liquid chromatography

Cocaethylene (benzoylecgonine ethyl ester or ethyl cocaine) is a transesterification product of cocaine and ethanol that has been observed in the urine of individuals using these drugs in combination. There is evidence that cocaethylene is pharmacologically active, and its formation in vivo may contribute to the toxicity of cocaine. A new method is presented here which enables the quantification of cocaethylene and cocaine, as well as the cocaine metabolites benzoylecgonine and norcocaine in liver tissue. This method utilizes high-performance liquid chromatography with uv detection (235 nm), and the propyl ester of cocaine is used as an internal standard. Liver homogenates are first buffered with 0.1 N dibasic potassium phosphate (pH 9.1) and then extracted with methylene chloride:isopropanol (9:1). Extraction efficiencies were approximately 75-85% for the compounds of interest. The coefficient of variation for replicate determinations (N = 10) of cocaethylene concentration was 5.75%, with comparable values obtained for cocaine, norcocaine, and benzoylecgonine. The detection limit for cocaethylene, based on a peak height threefold greater than background noise, was approximately 1.7 ng of injected compound. Using this method, it was demonstrated that cocaethylene is present in mouse liver following cocaine and ethanol administration, with an apparent rapid rate of formation and elimination.

Preservation of glucuronidation in carbon tetrachloride-induced acute liver injury in the rat☆

Abstract The influence of carbon tetrachloride on several routes of drug metabolism has been investigated in the rat in vivo , in isolated perfused livers, and in hepatic microsomal preparations to evaluate the hypothesis that hepatic glucuronyl transferase activity is preserved when mixed-function oxidase activity is impaired by this hepatotoxin. Impaired oxidative metabolism after acute administration of carbon tetrachloride was confirmed in vivo by a 65 per cent reduction in the rate of elimination of 14 CO 2 in breath after [ 14 C]aminopyrine administration and a 58 per cent reduction in the clearance of lorazepam in the whole animal. In the isolated perfused livers of control rats, glucuronide metabolism of lorazepam accounted for 26 per cent of its overall elimination; thus, by inference, oxidative metabolism accounted for the remainder. Carbon tetrachloride pretreatment resulted in a 63 per cent reduction in total lorazepam clearance. In microsomal preparations, cytochrome P-450 concentration, cytochrome P-450 reductase activity, and activities of o -demethylation of p -nitroanisole and hydroxylation of aniline were reduced by 63, 32, 85 and 95 per cent, respectively, after exposure to carbon tetrachloride. In contrast, in the carbon tetrachloride-damage isolated perfused liver the proportion of lorazepam conjugated to lorazepam glucuronide increased from 26 to 43 per cent of the dose administered. Furthermore, in vitro microsomal glucuronidation of o -aminophenol was not decreased by carbon tetrachloride pretreatment, while glucuronidation of p -nitrophenol actually increased significantly by 49 per cent. Solubilization of microsomes with Triton X-100 resulted in a 10.4-fold increase in glucuronyl transferase activity in control microsomes, but in only a 5.7-fold increase in microsomes from carbon tetrachloride-treated rats. This suggests that carbon tetrachloride enhanced basal glucuronidating activity but decreased the total amount of enzymes present. These overall results suggest that microsomal glucuronidation activity is spared in an experimental liver injury in which oxidative metabolism is impaired.

Principles of toxicology

Principles of toxicology : , Principles of toxicology : , کتابخانه دیجیتال جندی شاپور اهواز

Methyphenidate-induced hepatotoxicity in mice and its potentiation by β-adrenergic agonist drugs

Abstract Methyphenidate hydrochloride, when adminitered as a single 75 to 100 mg/kg i.p. dose, was found to produce hepatic necrosis in male ICR mice. Peak hepatotoxicity, as measured by serum ALT elevation, ooccurred 16 hours post-treatment while maximal histopathological evidence of hepatotoxicity occurred 24–48 hours after the methylphenidate dose. Liver injury measured by either method was essentially nonexistent for dosages ⩽ 50 mg/kg in male mice, and was only minimally evident in female mice at the highest dosage testable. Co-treatment of mice with either α 1 -or α 2 -madrenergic agonist drugs had no meaningful effect on methylhenidate-induced hepatotocitity. In contrast, the β-adrenergic agonist drug isoproterenol produced a striking potentiation of the liver injury, and shifted the apparent threshold for toxicity approximately 5- to 10-fold. Co-adminitration of methyphenidate with the mixed α/gb-adrenergic agonist dobutamine or with the β2- selective agonists metaproterenol, ritodrine or terbutaline produced a similar prtentiation of toxicity. Parallel tests with β-adrenergic antagonists revealed that the potentiation by isoproterenol could be significantly diminished by a single dose of the non-selective β-adrenoreceptor blocking drug nadolol or the b 2 -selective antagonist ICI-118,551, but not the b 1 -selective antagonist metoprolol. Collectively, these observations suggest that potentiation of methylpenidate hepatotoxicity occurs through stimulation of b 2 -adrenoreceptors. Mice co-treated with isoproterenol were found to have substantially higher serum and liver methylphenidate levels following the methylphenidate dose, and significant increases were also observed in the area-under-the curve (AUC) for methylphenidate in both tissues of isoproterenol co-treatedd mice. The results of this study suggest that β 2 -adrenergic agonist drugs are capable of potentiating methylphenidate-induced hepatotoxicity in mice by increasing hepatic methylphenidate concentrations.

Comparison of covalent binding from halothane metabolism in hepatic microsomes from phenobarbital-induced and hyperthyroid rats

1. Hepatic microsomal suspensions from rats pretreated with saline, phenobarbital or triiodothyronine were incubated with 14C-halothane under aerobic and anerobic conditions. 2. Metabolism of halothane by microsomes from phenobarbital-induced rats under anaerobic conditions resulted in covalent binding of 14C to microsomal lipids, and to a lesser extent, microsomal proteins, as seen in previous studies. Covalent binding was decreased with incubation under aerobic conditions. 3. Metabolism of halothane by microsomal suspensions from hyperthyroid rats produced much less covalent binding to microsomal lipids and proteins, with binding similar to, or less than, that observed with microsomes from saline-treated rats. The covalent binding of halothane to protein of microsomes from hyperthyroid rats was dependent upon metabolism, and was inhibited by SKF 525A, reduced glutathione, or cytosol. 4. The in vitro observations with respect to covalent binding are inconsistent with previous reports on halothane hepatotoxicity in hyperthyroid rats in vivo. This inconsistency and the relatively small extent of covalent binding with microsomes from hyperthyroid rats observed, suggests that covalent binding is not an important mechanism of halothane hepatotoxicity in the hyperthyroid rat model.