Biomedical subjects

R D Harbison

Publications and source records attributed to R D Harbison.

At least 19 recordsLinked to original sources

PubMed2001

Comparison of base-excision repair capacity in proliferating and differentiated PC 12 cells following acute challenge with dieldrin.

Dieldrin, an organochlorine pesticide and known neurotoxicant, is ubiquitously distributed in the environment. Dieldrin depletes brain monoamines in some animal species and is toxic for dopaminergic neurons in vitro. Dieldrin interferes with mitochondrial electron transport and increases generation of superoxide anion. Reactive oxygen species have been shown to produce oxidative lesions to DNA bases, i.e., 8-hydroxy-2'-deoxyguanosine (8-oxodGuo). Accumulation of 8-oxodGuo has been shown to be promutagenic in proliferating cells, and can lead to degeneration in fully differentiated cells. The objective of this study was to determine the effects of dieldrin exposure on the activity of the enzyme responsible for removing 8-oxodGuo, OGG1, from undifferentiated (untreated with NGF) and differentiated (NGF-treated) PC 12 cells. Proliferating PC 12 cells exhibited a mild upregulation of glycosylase activity, reaching a maximum by 1 h and returning to baseline by 6 h. Differentiated (+) NGF cells showed a time-dependent decline in activity reaching a nadir at 3 h with a return towards baseline by 6 h. Levels of the damaged base, 8-oxodGuo, in the differentiated PC12 cells appeared to be regulated by the activity of OGG1. In contrast, levels of the damaged base in actively proliferating cells were independent of the OGG1 activity. This difference between actively dividing and differentiated cells in the regulation of base-excision repair and DNA damage accumulation explains, in part, the vulnerability of postmitotic neurons to oxidative stresses and neurotoxins.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2001

Heavy metal hazards of Asian traditional remedies.

In recent years there has been an increase in the use of traditional Asian medicines. It is estimated that 30% of the US population is currently using some form of homeopathic or alternative therapy at a total cost of over $13 billion annually. Herbal medications are claimed and widely believed to be beneficial; however, there have been reports of acute and chronic intoxications resulting from their use. This study characterizes a random sampling of Asian medicines as to the content of arsenic, mercury, and lead. Traditional herbal remedies were purchased in the USA, Vietnam, and China. The Asian remedies evaluated contained levels of arsenic, lead, and mercury that ranged from toxic (49%) to those exceeding public health guidelines for prevention of illness (74%) when consumed according to the directions given in or on the package. Heavy metals contained in Asian remedies may cause illness of unknown origin and result in the consumption of health care resources that are attributable to other causes. The public health hazards of traditional herbal Asian remedies should be identified and disclosed.

Arsenic↗

PubMed2001

Organ-specific differences in 8-oxoguanosine glycosylase (OGG1) repair following acute treatment with benzo[a]pyrene.

The lung has been shown to be a target organ for the deleterious effects of Benzo[a]pyrene (B[a]P), regardless of the route of exposure. 8-hydroxy-2'-deoxyguanosine (oxo8dG) is a mutagenic lesion formed in DNA following exposure to B[a]P. The objective of this study was to determine the capacity of different organs to repair oxo8dG following intraperitoneal (i.p.) treatment with B[a]P. Male Spraque-Dawley rats were administered 20 mg/kg B[a]P i.p., 2 times/day for 5 days. A 26% decrease in the capacity to remove oxo8dG was observed in lung tissue at 72 hours and recovered 20% above control values at 120 hours. The capacity of the liver and kidney remained at baseline for all time points analyzed. A 7-fold increase in oxo8dG was observed in the lung at 72 hours. This study demonstrates that organ-specific differences exist in the capacity to remove oxo8dG and further demonstrates the susceptibility of lung tissue to the effects of B[a]P.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed1995

Mechanistic studies on the potentiation of carbon tetrachloride hepatotoxicity by methamphetamine.

Recent studies have shown that methamphetamine is capable of potentiating the hepatotoxicity of carbon tetrachloride in mice. In the present study, it was found that this potentiation is sensitive to changes in the timing of the methamphetamine dose relative to the administration of carbon tetrachloride. Potentiation of hepatotoxicity, measured using serum alanine aminotransferase (ALT) activity, was observed only if the dose of methamphetamine (15 mg/kg, i.p.) was given with, or 3 h after, the carbon tetrachloride dose (0.005 ml/kg, i.p.). No increase in carbon tetrachloride hepatotoxicity was evident when methamphetamine was administered 3 h before the carbon tetrachloride dose, or when given 6 or more hours after carbon tetrachloride. Increased covalent binding of carbon tetrachloride to proteins and lipids, shown previously to occur when methamphetamine and carbon tetrachloride are administered together, was not observed when methamphetamine was administered 3 h after the carbon tetrachloride dose and could not, therefore, account for the increased toxicity resulting from this treatment regimen. Pretreatment with the Kupffer cell inhibitor gadolinium chloride (10 mg/kg, i.v.) significantly diminished the potentiation of carbon tetrachloride hepatotoxicity by methamphetamine, suggesting that potentiation by methamphetamine involves, at least in part, a stimulation of Kupffer cells. Mice administered a methamphetamine pretreatment regimen known to induce behavioral sensitization displayed an enhanced potentiation of carbon tetrachloride hepatotoxicity, i.e. the extent of potentiation by methamphetamine was increased and the methamphetamine dose required for potentiation was diminished. Mice pretreated with a methamphetamine sensitization regimen were also found to be more responsive to the effects of morphine to enhance carbon tetrachloride hepatotoxicity. These observations suggest that there are important CNS, as well as hepatic, components in the potentiation of carbon tetrachloride-induced liver injury by methamphetamine and perhaps other drugs.

Alanine Transaminase↗

PubMed1995

Influence of soil half-life on risk assessment of carcinogens.

Risk estimates for contaminants in soil are currently calculated assuming that concentrations remain unchanged over time. In reality, biological and physicochemical processes can substantially diminish contaminant concentrations in soil. For exposure periods typically evaluated in USEPA risk assessments, failure to consider the decline in contaminant levels from environmental transport and degradation can result in a significant overestimation of the average daily dose of toxicant. This overestimation may be up to 2- to 3-fold for compounds with long half-lives (15-20 years) in soil and as much as 40-fold for compounds with short half-lives (0.5 years). Overestimation of dosages affects estimation of cancer risks because of the assumption that the probability of cancer increases directly with the cumulative dose of carcinogen. Thus, assuming static contaminant concentrations in soil adds unacknowledged conservatism to cancer risk estimates and target concentration limits. Furthermore, as significant time may elapse before future-use scenarios could possibly occur, soil half-life can affect the estimation of noncarcinogenic health hazards as well. Therefore, an increase in target concentration limits for some compounds could be allowed and corresponding remediation costs reduced by considering how soil half-life changes the dosage calculation. Specific examples of the influence of soil degradation rates on estimates of cancer risk are presented and the degree of added conservatism imparted to risk assessments through assumption of static site contaminant levels is discussed. Considering the potential importance of this parameter for risk assessment and risk management decisions, soil degradation of contaminants under site-specific conditions should be performed whenever possible and incorporated into the risk assessment exercise. When the soil degradation rate cannot be measured or reliably predicted, an estimate of the degree of conservatism should be made to provide risk managers with an appreciation of the degree of uncertainty in the calculation of risk.

Animals↗

PubMed1995

Exacerbation of carbon tetrachloride-induced liver injury in the rat by methamphetamine.

The effect of methamphetamine cotreatment on carbon tetrachloride-induced liver toxicity was examined in male Sprague-Dawley rats. Concurrent administration of methamphetamine was found to greatly increase the extent of liver injury resulting from carbon tetrachloride treatment, as indicated both by measurement of serum alanine aminotransferase (ALT) activity and from direct histopathologic examination. Concurrent administration of methamphetamine doses less than 10 mg/kg (i.p.), or administration of methamphetamine either before (-3 h) or after (3-9 h) the carbon tetrachloride dose, did not significantly increase liver injury from carbon tetrachloride. These observations indicate that the potentiation by methamphetamine of carbon tetrachloride hepatoxicity previously observed in the mouse also occurs in the rat, and that the timing of the methamphetamine and carbon tetrachloride doses is critical for the interaction.

Alanine Transaminase↗

PubMed1994

Methylphenidate-induced hepatotoxicity in mice and its potentiation by beta-adrenergic agonist drugs.

Methylphenidate hydrochloride, when administered 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 elevations, occurred 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 < or = 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 alpha 1- or alpha 2-adrenergic agonist drugs had no meaningful effect on methylphenidate-induced hepatotoxicity. In contrast, the beta-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-administration of methylphenidate with the mixed alpha/beta-adrenergic agonist dobutamine or with the beta 2-selective agonists metaproterenol, ritodrine or terbutaline produced a similar potentiation of toxicity. Parallel tests with beta-adrenergic antagonists revealed that the potentiation by isoproterenol could be significantly diminished by a single dose of the non-selective beta-adrenoreceptor blocking drug nadolol or the beta 2-selective antagonist ICI-118,551, but not the beta 1-selective antagonist metoprolol. Collectively, these observations suggest that potentiation of methylphenidate hepatotoxicity occurs through stimulation of beta 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-treated mice. The results of this study suggest that beta 2-adrenergic agonist drugs are capable of potentiating methylphenidate-induced hepatotoxicity in mice by increasing hepatic methylphenidate concentrations.

Adrenergic alpha-Agonists↗

PubMed1994

Methamphetamine potentiation of carbon tetrachloride hepatotoxicity in mice.

Previous studies have indicated that adrenergic agents may potentiate the hepatotoxicity of compounds such as CCl4. Methamphetamine is a powerful central nervous system stimulating drug which also possesses significant adrenergic activity, and its effects on CCl4 hepatotoxicity were examined in male ICR mice. Cotreatment of mice with methamphetamine (15 mg/kg i.p.) resulted in a significant increase in the hepatocellular necrosis produced by minimally toxic to moderately toxic doses of CCl4 (0.005-0.02 ml/kg i.p.), as indicated by changes in serum alanine aminotransferase activity and by histopathologic examination. Methamphetamine alone at this dosage was not hepatotoxic. The ability of methamphetamine to potentiate CCl4 hepatotoxicity was dose-related and became statistically significant at methamphetamine doses of 10 mg/kg or greater. Pretreatment of animals with either the selective alpha-1 adrenoreceptor antagonist prazosin (5 mg/kg i.p.) or the selective alpha-2 adrenoreceptor antagonist yohimbine (5 mg/kg i.p.) blocked the methamphetamine potentiation. The increase in CCl4 toxicity produced by methamphetamine was not associated with an increase in hepatic concentrations of either CCl4 or one of its major metabolites, chloroform. The increase in toxicity was associated, however, with increases in the in vivo covalent binding of radiolabeled CCl4 to both hepatic proteins and lipids. The cause of the increased covalent binding was not identified, but did not appear to be related to methamphetamine-induced hepatic glutathione suppression. The results of this study suggest that methamphetamine potentiates CCl4 through an adrenoreceptor-related mechanism that may involve either the increased production or diminished conjugation of the reactive metabolites normally formed during the metabolism of CCl4.

Alanine Transaminase↗

PubMed1993

Phenylpropanolamine potentiation of acetaminophen-induced hepatotoxicity: evidence for a glutathione-dependent mechanism.

Pretreatment of male ICR mice with the adrenergic agonist phenylpropanolamine (200 mg/kg, ip) resulted in a marked potentiation of hepatotoxicity produced by acetaminophen (400 mg/kg, ip). Enhanced liver necrosis with phenylpropanolamine pretreatment was evident both by measurement of serum aminotransferase activity and by histopathologic examination. Several lines of experimental evidence suggest this interaction is a result of the hepatic glutathione depression produced by alpha-adrenergic compounds, which adds to the glutathione depression caused by toxic, or nearly toxic, doses of acetaminophen. First, the potentiation of acetaminophen hepatotoxicity was time-dependent, being observed only when phenylpropanolamine was administered as a 3-hr pretreatment and not when given 1 hr before, with, or 3 hr after acetaminophen. The 3-hr interval between phenylpropanolamine and acetaminophen doses corresponds to the characteristic lag period required for alpha-adrenergic agents (including phenylpropanolamine) to produce significant and maximal effects on hepatic glutathione content. Second, dose-response relationships for phenylpropanolamine and acetaminophen were such that increased toxicity was observed only when the interaction was sufficient to lower hepatic glutathione concentrations below a level regarded as critical in preventing acetaminophen-induced hepatotoxicity. Third, when animals were pretreated with two nonadrenergic depletors of hepatic glutathione, diethylmaleate (125 mg/kg, ip) or the glutathione synthesis inhibitor buthionine sulfoximine (222 mg/kg, ip), at doses producing glutathione depletion approximating that observed with the adrenergic agents, acetaminophen hepatotoxicity was potentiated to the same extent. From these observations it is postulated that a variety of adrenergic compounds known to deplete hepatic glutathione by a moderate 30-50% may potentiate the hepatotoxicity of acetaminophen and possibly other hepatotoxic compounds for which glutathione conjugation is an important detoxification pathway.

Acetaminophen↗

PubMed1993

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.

Cohort Studies↗

PubMed1992

Cocaethylene hepatotoxicity in mice.

Cocaethylene is a novel metabolite of cocaine formed in the presence of ethanol. When administered to ICR male mice in dosages ranging from 10 to 50 mg/kg, i.p., cocaethylene was found to produce dose-dependent hepatic necrosis in the midlobular zone (zone 2). Severity of the lesion was maximal 12-24 hr after administration. A transient but significant decrease in hepatic glutathione content was observed 1 hr after cocaethylene administration. Pretreatment with the cytochrome P450 inhibitors cimetidine (200 mg/kg, i.p., in divided doses) or SKF 525A (50 mg/kg, i.p.) diminished toxicity. Pretreatment of mice with the esterase inhibitor diazinon (10 mg/kg, i.p.) increased cocaethylene hepatotoxicity, as did pretreatment with the cytochrome P450 inducing agents phenobarbital (80 mg/kg/day, i.p., for 3 days) or beta-naphthoflavone (40 mg/kg/day, i.p., for 3 days). Phenobarbital pretreatment also caused a shift in the morphologic site of necrosis from midzonal to peripheral lobular (zone 1) regions. The type of hepatic lesion produced by cocaethylene, its morphologic distribution (including the shift with phenobarbital treatment), the potency of cocaethylene in producing this effect, and the apparent requirement of oxidative metabolism for hepatoxicity were all remarkably similar to observations with its parent compound, cocaine, in this and earlier studies. This suggests that these compounds produce liver toxicity through the same or similar mechanisms.

Alanine Transaminase↗

PubMed1992

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.

Animals↗

PubMed1992

Cocaine hepatotoxicity: influence of hepatic enzyme inducing and inhibiting agents on the site of necrosis.

Cocaine-induced hepatotoxicity has been reported in human beings and is well documented in mice. One interesting feature of this toxicity that appears to be common to both species is an apparent shift in the intraacinar site of necrosis under circumstances known to alter cocaine metabolism. However, the evidence in human subjects is limited, and studies elucidating the mechanism of this phenomenon cannot be performed in human beings. Although future studies in mice may define the basis of this mechanism, the current evidence is a somewhat fragmented composite of studies using different mouse strains and enzyme-inducing agents. Therefore a comprehensive pathologic investigation was initiated for the purpose of identifying and establishing an animal model suitable for studying this phenomenon. In naive ICR mice a single 60 mg/kg dose of cocaine was found to produce midzonal (zone 2) coagulative necrosis. In mice whose oxidative metabolism had been increased with beta-ionone or in which esterase metabolism had been inhibited by diazinon, the severity of the toxicity was increased but the intraacinar origin of the lesion did not change. However, when the oxidative microsomal metabolism of ICR mice was induced by phenobarbital or beta-naphthoflavone, the acinar zone affected was dramatically different. Phenobarbital induction produced zone 1 necrosis, whereas beta-napthoflavone induction caused necrosis in zone 3. The site of necrosis corresponded with the distribution of cocaine, and its metabolites were identified with colloidal gold-conjugated antibody probes. The results of this study suggest that the agents shifting the location of cocaine-induced hepatic necrosis alter the intraacinar site of protein binding of cocaine and its metabolites.

Alanine Transaminase↗

PubMed1992

Effects of reproductive tract glutathione enhancement and depletion on ethyl methanesulfonate-induced dominant lethal mutations in Sprague-Dawley rats.

The effects of altering glutathione (GSH) levels in the male reproductive tract have been studied in an attempt to establish a link between chemical-induced perturbations in glutathione and susceptibility of spermatozoa to chemical insult. Tissue GSH levels were enhanced by a treatment regimen of N-acetylcysteine (NAC) (250 mg/kg, 4 treatments at 2 h intervals). With this treatment, GSH levels in liver, testis, caput epididymis, and cauda epididymis were elevated to 126%, 110%, 178%, and 136% of control values. Sexually mature male rats were then treated with NAC and challenged with a dose of EMS (100 mg/kg) to determine if enhanced tissue GSH would protect against EMS-induced dominant lethal mutations. Pretreatment with NAC significantly decreased the post-implantation loss from 7.05 +/- 0.57 with EMS alone to 5.28 +/- 0.47. Conversely, a dominant lethal assay was conducted using different doses of phorone pretreatment to determine the relative contribution of hepatic versus reproductive tract GSH in protecting against EMS-induced dominant lethal resorptions. Doses of 100 mg/kg and 250 mg/kg phorone significantly lowered both hepatic and reproductive tract GSH while 25 mg/kg lowered only hepatic GSH. These three dose levels were used as pretreatments in a dominant lethal study followed by a challenge administration of EMS (50 mg/kg), which is a threshold dose of EMS for producing dominant lethal mutations. Comparison against controls demonstrated a significant potentiation of fetal resorptions in all groups receiving phorone pretreatment, including the 25 mg/kg pretreatment group which only lowered hepatic GSH prior to EMS challenge. The results of these experiments indicate that GSH reserves in the male reproductive tract are insufficient to protect developing spermatozoa from damage by alkylating agents in the absence of hepatic GSH.

Acetylcysteine↗

PubMed1991

Examination of the role of catecholamines in hepatic glutathione suppression by cold-restraint in mice.

Cold-restraint stress was found to produce a depression in hepatic glutathione content and to elevate circulating catecholamine levels in four mouse strains--ICR, NIH, B6C3F1, and ND/4. Serum norepinephrine concentrations were significantly elevated after cold-restraint (2--3 h) in all strains, and serum epinephrine levels were increased in the B6C3F1 and ND/4 strains. In time-course studies conducted using ND/4 mice, the decline in hepatic glutathione concentrations was found to slightly precede increases in serum epinephrine and norepinephrine concentrations. Also, pretreatment with phentolamine, an alpha-adrenoreceptor antagonist compound shown in previous studies to block epinephrine-induced hepatic glutathione suppression, had no effect on glutathione losses from cold-restraint. These observations are inconsistent with catecholamines as sole mediators of cold-restraint induced hepatic glutathione depression. Two other endogenous substances elevated during stress, corticosteroids and glucagon, were found to diminish glutathione concentrations in the liver in ND/4 mice when administered exogenously. The effects of catecholamines (epinephrine), corticosteroids (hydrocortisone) and glucagon were not additive, i.e. the depression in glutathione when these agents were administered in combination was generally no greater than that induced when the most effective agent was administered alone. It is postulated that during cold-restraint stress multiple endogenous agents are released which are independently capable of causing a depression in hepatic glutathione content.

Animals↗

PubMed1991

Potentiation of carbon tetrachloride hepatotoxicity by phenylpropanolamine.

Hepatic necrosis produced by carbon tetrachloride (0.02, 0.06, or 0.20 ml/kg, ip) in mice was found to be potentiated by simultaneous cotreatment with phenylpropanolamine (200 mg/kg, ip), a drug with catecholamine-like pharmacologic effects. The ability to potentiate carbon tetrachloride-induced hepatic necrosis was shared by a compound with agonist effects relatively selective for alpha 2-adrenoreceptors (clonidine, 5 mg/kg, ip), but not by specific alpha 1-adrenoreceptor agonists (phenylephrine, up to 100 mg/kg, ip and methoxamine, up to 50 mg/kg, ip) or by the beta-adrenoreceptor agonist isoproterenol (up to 100 mg/kg, ip). Yohimbine (5 mg/kg, ip), a selective alpha 2-adrenoreceptor antagonist, completely blocked the potentiating effect of phenylpropanolamine on carbon tetrachloride hepatotoxicity, providing further evidence that the increased hepatotoxic response with phenylpropanolamine cotreatment was mediated through alpha 2-adrenoreceptor stimulation. Four potential mechanisms for phenylpropanolamine potentiation of liver injury from carbon tetrachloride were examined: (1) increased concentrations of carbon tetrachloride in the liver from greater absorption or altered distribution; (2) diminished food consumption leading to a starvation-like increase in responsiveness to carbon tetrachloride; (3) impaired detoxification through a depletion of hepatic glutathione content; and (4) enhanced toxicity produced by elevated core body temperature. None of these potential mechanisms was supported by the experimental results. It is concluded that phenylpropanolamine and related compounds potentiate carbon tetrachloride hepatotoxicity through a mechanism involving alpha 2-adrenoreceptor stimulation that has yet to be identified.

Animals↗

PubMed1991

Hepatic glutathione suppression by the alpha-adrenoreceptor stimulating agents phenylephrine and clonidine.

The effects of alpha-adrenoreceptor stimulation on hepatic glutathione content were examined in ICR male mice using a selective alpha 1-adrenoreceptor stimulating agent, phenylephrine, and a selective alpha 2-adrenoreceptor stimulating drug, clonidine. Phenylephrine produced a dose-dependent depression in hepatic glutathione levels when administered by the intraperitoneal (i.p.) route, with a maximum extent of depression of approximately 30% occurring in both male and female mice. Phenylephrine was ineffective by the intracerebroventricular route, indicating a peripheral site of action which would be consistent with the mechanism(s) suggested by earlier in vitro studies using rat liver. Clonidine, an alpha 2-adrenoreceptor stimulating agent, also depressed hepatic glutathione concentrations in a dose-dependent manner. The maximum extent of depression (approx. 45%) from clonidine administered by the i.p. route was somewhat greater than that from phenylephrine, and the apparent potency was about 10-fold greater. Unlike phenylephrine, clonidine was effective when administered by the intracerebroventricular route. Pretreatment of mice with phenylephrine (100 mg/kg, i.p.) resulted in a potentiation of hepatic necrosis from a mildly hepatotoxic dose of acetaminophen (400 mg/kg, i.p.). The results of these experiments suggest that the changes in glutathione homeostasis produced by alpha-adrenoreceptor stimulation may be sufficient to impair detoxification mechanisms.

Acetaminophen↗

PubMed1990

Depression of glutathione by cold-restraint in mice.

The effects of cold-restraint as a physiological stressor on the glutathione (GSH) content of the liver and other tissues were examined in male mice. Mice of the ICR, NIH, ND/4, and B6C3F1 strains subjected to cold-restraint for 2 or 3 h experienced a loss of hepatic GSH concentrations ranging from approximately 15 to 50%. Though 3 of these strains (ICR, NIH, and B6C3F1) experienced hypothermia as result of the cold-restraint treatment, with average decreases in core body temperature ranging from 3.3 to 9.8 degrees C, hepatic GSH levels were depressed in the ND/4 mouse in the absence of changes in core body temperature. The ability of cold-restraint as a stressor to diminish hepatic GSH therefore could not be attributed simply to hypothermia. The decrease in hepatic GSH from cold-restraint in ND/4 mice was paralleled by a decrease in non-protein sulfhydryl (NPSH) content of the liver. In addition to its effects on liver GSH and NPSH concentrations, 1.5 h of cold-restraint stress significantly depressed plasma, heart, kidney, and lung NPSH concentrations. The extent of NPSH depression was equivalent to the GSH depression in the liver, heart, and kidney, despite the observation that the normal contribution of GSH to total NPSH content in these tissues ranged from a high of 89% (liver) to a low of 49% (heart). These results with cold-restraint in the ND/4 mouse suggest that other stressors may significantly depress cellular concentrations of GSH and other thiols, and may thereby render the affected tissues more susceptible to the toxicity of free radicals, electrophilic xenobiotic metabolites, or reactive oxygen species.

Animals↗