Biomedical subjects

R D Harbison

Publications and source records attributed to R D Harbison.

114 records · Page 7Linked to original sources

PubMedDate not supplied

Potentiation of chlorinated hydrocarbon toxicity by 2,5-hexanedione in primary cultures of adult rat hepatocytes.

Primary cultures of adult rat hepatocytes were used to investigate potentiation of halocarbon-induced hepatotoxicity by aliphatic ketones. Male Sprague-Dawley rats were pretreated with corn oil or 2,5-hexanedione (HD; 15 mmol/kg, po) in corn oil. Eighteen hours later the hepatocytes were isolated and cultured in Williams' Medium E and exposed to several concentrations of the hepatotoxicants carbon tetrachloride, chloroform, deutero-chloroform, or 1,1,2-trichloroethane. The cytotoxicity of these halocarbons as measured by release of the cytosolic enzyme lactate dehydrogenase into the culture medium was both time- and concentration-dependent. Halocarbon-induced cytotoxicity was exacerbated in cells isolated from HD-pretreated rats with significant increases in LDH release over cells isolated from corn oil-pretreated rats. In addition, chloroform was significantly more toxic than deutero-chloroform in hepatocytes from either corn oil- or HD-pretreated rats. Primary monolayer cultures were useful for studying ketone-induced potentiation, halocarbon-induced hepatocellular toxicity, and the mechanisms by which these effects occur.

Animals↗

PubMedDate not supplied

Role of biotransformation in the potentiation of halocarbon hepatotoxicity by 2,5-hexanedione.

2,5-Hexanedione (2,5-HD) pretreatment potentiated CHCl3-induced hepatotoxicity. 2,5-HD significantly increased hepatic cytochrome P-450, NADPH cytochrome c reductase, aniline hydroxylation, p-nitroanisole O-demethylation, and aminopyrine N-demethylation in both male and female mice. 2,5-HD pretreatment potentiated CHCl3-induced centrilobular necrosis and increased serum alanine amino transferase (ALT) activity by 20 times more than CHCl3 alone. Similarly, 2,5-HD pretreatment potentiated CDCl3-induced hepatotoxicity as well as CCl4-induced hepatotoxicity in male mice, but did not potentiate trichloroethylene-, 1,1,2-trichloroethane-, or perchloroethylene-induced hepatotoxicity. In female mice, 2,5-HD pretreatment potentiated CHCl3- and CDCl3-induced hepatotoxicity as well as trichloroethylene-, 1,1,2-trichloroethane-, and carbon tetrachloride-induced hepatotoxicity, but not perchloroethylene-induced hepatotoxicity. 2,5-HD pretreatment had no preferential effect on either CHCl3- or CDCl3-induced hepatotoxicity in females. However, phenobarbital pretreatment did differentiate CHCl3- and CDCl3-induced hepatotoxicity in females. 2,5-HD-induced potentiation of halocarbon hepatotoxicity is sex dependent.

Alanine Transaminase↗

PubMedDate not supplied

Alpha1-adrenergic receptors and their significance to chemical-induced nephrotoxicity--a brief review.

Stimulation of alpha-adrenergic receptors by cold stress or adrenergic agents has been shown to potentiate the toxicity of numerous toxicants. Several lines of evidence indicate that this interaction is dependent on glutathione depression and increased cytosolic Ca2+ concentrations produced by alpha1-adrenergic compounds. In this report, evidence is provided in support of the mechanism of adrenoreceptor-mediated potentiation of nephrotoxicity. Alpha1-adrenergic agonists are shown to potentiate the toxicity of nephrotoxicants that exert their toxic effects via glutathione conjugation or Ca2+ deregulation. This review summarizes the effects of the alpha1-adrenergic agonist, phenylephrine, at enhancing the toxicity of 2-bromohydroquinone, 1,2-dibromoethane, and cis-diammineplatinum(II) dichloride.

Animals↗

PubMedDate not supplied

Human microsomal N-oxidative metabolism of cocaine.

The N-oxidative metabolism of cocaine has been described previously in some detail in the mouse, and is associated with hepatotoxic effects of cocaine in this species. As part of an effort to determine whether this metabolism-dependent toxicity is relevant to clinical reports of liver injury from cocaine, the in vitro N-oxidative metabolism of cocaine was examined in microsomal suspensions obtained from human liver specimens. Human hepatic microsomal suspensions were capable of metabolizing cocaine to norcocaine, and norcocaine to N-hydroxynorcocaine, which is the sequential oxidative metabolism observed in mice to lead to toxic metabolite formation. Additionally, incubation of 4-[3H]cocaine with human hepatic microsomal suspensions resulted in the formation of a metabolite that bound irreversibly to microsomal protein. Each of these reactions was inhibited or abolished by gassing the incubation mixture with carbon monoxide, omitting NADPH, or adding the cytochrome P-450 inhibitors SKF 525-A (50 microM) or n-octylamine (3 mM). Competing microsomal esterase activity reduced the apparent rate of N-demethylation of cocaine by 50%, but had much less effect on the N-hydroxylation of norcocaine. In general, apparent KM values for both the N-demethylation and N-hydroxylation reactions in human liver microsomal suspensions were greater than those observed in comparable incubations using mouse hepatic microsomal suspensions, whereas Vmax rates were lower. The extent of irreversible (i.e. nonextractable) binding of cocaine following its metabolism in vitro was comparable between human and mouse microsomal suspensions, however. Similarities in the N-oxidative metabolism of cocaine suggest that humans and mice share the same bioactivation mechanism of cocaine-induced liver injury.

Adolescent↗

PubMedDate not supplied

Covalent binding of procainamide in vitro and in vivo to hepatic protein in mice.

Procainamide (PA) formed reactive metabolites capable of covalently binding to protein both in vivo and in vitro. The in vitro covalent binding of PA to washed hepatic microsomal protein prepared from control male mice was dependent upon mixed-function oxidase activity. The binding was proportional with time and protein concentration. Glutathione and SKF 525-A inhibited the in vitro covalent binding by 88 and 51%, respectively. The addition of NaF to the incubation medium produced a concentration-dependent decrease in covalent binding. Covalent binding of N-acetylprocainamide in vitro was 90% less than that of procainamide and was not increased by NaF. The in vivo covalent binding of PA to hepatic protein in male mice was increased with phenobarbital and 3-methylcholanthrene pretreatment, resulting in increase in binding of 29 and 56%, respectively, compared to control mice. Pretreatment of mice with SKF 525-A inhibited binding by 39%. Depletion of hepatic glutathione with diethyl maleate pretreatment increased the amount of covalent binding in vivo. Bioactivation of PA by hepatic microsomal enzymes in the mouse produces a metabolite capable of covalent interactions with cellular macromolecules.

Acecainide↗

PubMedDate not supplied

Inhibition by ethanol of the metabolism of cocaine to benzoylecgonine and ecgonine methyl ester in mouse and human liver.

Previous studies have suggested that the esteratic metabolism of cocaine to benzoylecgonine may be inhibited by the presence of ethanol. In this study, the effects of ethanol on the esteratic metabolism of cocaine to benzoylecgonine and to ecgonine methyl ester were examined in vitro using 60,000g supernatant from mouse and human liver. The addition of ethanol (40 mM) to an incubation mixture containing cocaine (24 microM) resulted in substantial decreases in benzoylecgonine and ecgonine methyl ester formation in liver from both species. Sodium fluoride (40 mM), included in the experiment as a positive control, also produced marked inhibition of cocaine metabolism to benzoylecgonine and ecgonine methyl ester. Additional studies were conducted in vivo in which mice were administered cocaine (50 mg/kg, ip) with or without ethanol pretreatment (3 g/kg by gavage). Ethanol pretreatment resulted in 2- to 3-fold increases in peak hepatic concentrations of cocaine, ecgonine methyl ester, and the N-oxidative metabolite norcocaine, and the areas under the hepatic concentration vs. time curve (AUCs) for these compounds were doubled. In contrast, the hepatic concentrations and AUC for benzoylecgonine were halved. These observations are consistent with an inhibition in vivo of esteratic metabolism of cocaine to benzoylecgonine, resulting in higher cocaine levels and metabolism through alternative pathways. Such an interaction may be of importance in the reported effects of ethanol to enhance the activity and toxicity of cocaine.

Animals↗