Biomedical subjects

R C James

Publications and source records attributed to R C James.

At least 37 records · Page 2Linked to original sources

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↗

PubMed1990

Cocaine toxicity in cultured rat hepatocytes.

Cocaine hydrochloride was added to primary cultures of hepatocytes isolated from naive and phenobarbital-induced (80 mg/kg i.p. for 3 d) Sprague-Dawley rats. Cocaine was cytotoxic, as measured by lactate dehydrogenase release, to cells from naive rats in concentrations of 1 mM or greater. Phenobarbital induction greatly increased the cytotoxic potency of cocaine in vitro, with nearly complete loss of cell viability at cocaine concentrations in culture as low as 0.01 mM. The addition of 10 microM SK&F-525-A to the cultures blocked cocaine cytotoxicity in cells from both naive and phenobarbital-induced rats. These results suggest that the metabolic pathways leading to cocaine hepatotoxicity identified in the mouse also exist in the rat hepatocyte.

Animals↗

PubMed1989

The pharmacokinetics of 2,2',5,5'-tetrachlorobiphenyl and 3,3',4,4'-tetrachlorobiphenyl and its relationship to toxicity.

The pharmacokinetics of two toxicologically diverse tetrachlorobiphenyls (TCBs) were measured in mice. After dosing to apparent steady-state conditions, 2,2',5,5'-TCB was found to have a tissue elimination half-life of between 1.64 and 2.90 days. The half-life of 3,3',4,4'-TCB was similar, ranging from 1.07 to 2.60 days. Systemic clearance and volume of distribution estimates were also similar for the two TCB isomers. The 3,3',4,4'-isomer had a substantially greater partitioning from serum into adipose, liver, and thymic tissues. With dosing regimens developed using these measured pharmacokinetic parameters, experiments were undertaken to compare toxic potency of these two TCBs when similar tissue concentrations of the two isomers were achieved in target and storage tissues. These studies demonstrated that thymic atrophy occurs at lower 3,3',4,4'-TCB doses and tissue concentrations than those required to produce hepatotoxicity. These two organ toxicities were produced only by 3,3',4,4'-TCB despite the fact that equivalent or higher tissue concentrations of 2,2',5,5'-TCB were achieved in vivo in all tissues. We conclude that the in vivo difference in the toxic potency of these two TCB isomers does not result from the significant differences in their tissue disposition, elimination, and ultimate bioaccumulation.

Adipose Tissue↗

PubMed1989

Depression of hepatic glutathione by opioid analgesic drugs in mice.

The ability of morphine and other opioid analgesic drugs to diminish hepatocellular glutathione (GSH) concentrations was examined in ICR mice. When administered intraperitoneally, morphine, hydromorphone, ethylmorphine, l-alpha-acetylmethadol (LAAM), and meperidine all caused a significant decrease in hepatic GSH concentrations in male mice while codeine, methadone, butorphanol, nalbuphine, and pentazocine were without effect even at doses up to those approaching acute lethality. Depression of hepatic GSH equivalent to that observed after ip administration could be elicited by icv administration of small doses of morphine, ethylmorphine, and hydromorphone. LAAM and meperidine were ineffective following icv administration in these experiments. The discrepancy between results following ip versus icv administration of LAAM and meperidine suggests that hepatic metabolism of some opioids may be important for their activity in the CNS, as both norLAAM and normeperidine diminished hepatic GSH when administered by the icv route. The opioid-induced lowering of hepatic GSH does not appear to be sex-dependent since morphine and LAAM produced qualitatively and quantitatively similar effects on hepatic GSH in female mice. Morphine administered icv produced a substantial increase in the hepatotoxicity of two compounds dependent upon GSH for detoxification, acetaminophen and cocaine, as measured by serum alanine aminotransferase activities. These observations indicate that a number of opioid analgesic drugs have the potential to diminish hepatic GSH. Further, these results support earlier studies which indicate that central opioid effects on hepatic GSH are mediated through mu-opioid receptor stimulation. Last, these studies suggest that a centrally initiated opioid action on hepatic GSH may significantly influence the susceptibility of the liver to the effects of some hepatotoxic agents.

Alanine Transaminase↗

PubMed1989

Antagonism of bromobenzene-induced hepatotoxicity by the alpha-adrenoreceptor blocking agents phentolamine and idazoxan: role of hypothermia.

A recent study from our laboratory revealed that cotreating mice with the alpha-adrenoreceptor antagonists phentolamine and idazoxan markedly diminished bromobenzene-induced hepatotoxicity. Subsequent studies also revealed that such cotreatment does not alter the pharmacokinetic disposition of bromobenzene in mice nor its bioactivation to reactive metabolites. In the present study, the possible role of hypothermia in the phentolamine antagonism of bromobenzene-induced hepatotoxicity was investigated. Bromobenzene alone caused a significant, dose-related hypothermia. The high dosage regimen (10 mg/kg per dose) of phentolamine or idazoxan that had been found to be hepatoprotective in earlier studies potentiated this hypothermia and more than doubled the net decrease in core body temperature experienced by the animals. Placing mice receiving bromobenzene in an environment with an ambient temperature of 10 degrees C likewise increased the hypothermia experienced by animals receiving bromobenzene. The magnitude of the net change in core body temperature elicited by exposure to cold was similar to but slightly less than the net change produced by cotreatment with either alpha-adrenoreceptor antagonist and the magnitude of the hepatoprotection this procedure provided against bromobenzene hepatotoxicity was equivalent to that observed with phentolamine cotreatment. In contrast, a lower dosage regimen of either adrenoreceptor antagonist (2.5 mg/kg per dose) resulted in no additional hypothermia yet still produced a near maximal antagonism of bromobenzene-induced hepatotoxicity. Further, increasing the ambient temperature to 30 degrees C completely reversed the phentolamine-induced (10 mg/kg per dose) increase in hypothermia, but did not affect phentolamine's antagonism of the bromobenzene-induced changes in hepatic glutathione levels, serum alanine aminotransferase activity, or 24-hr mortality. Therefore, we conclude that while the hepatoprotective intervention of phentolamine can be mimicked by an exposure to cold that results in hypothermia, it is clear that alpha-adrenergic antagonists diminish the hepatotoxicity induced by bromobenzene by a mechanism that is independent of hypothermia.

Adrenergic alpha-Antagonists↗

PubMed1989

Perturbation of glutathione by a central action of morphine.

A series of studies were conducted in order to further characterize the previously reported effect of morphine to diminish hepatocellular concentrations of glutathione (GSH) in mice. Naive ICR mice administered morphine (i.p.) in doses up to 1000 mg/kg had diminished hepatic GSH concentrations, with a maximum depletion of approximately 50% occurring at doses of 250 mg/kg or greater. No such effect from an acute challenge with morphine was observed in morphine-tolerant mice. The intracerebro-ventricular administration of the opioid receptor antagonist naltrexone (250 micrograms) completely blocked the hepatic GSH depression resulting from the systemic (i.p.) administration of morphine (100 mg/kg). When morphine (100 micrograms) was administered by the i.c.v. route, GSH concentrations in liver and plasma were significantly altered while heart and kidney were unchanged. Variable responses to i.c.v. morphine were obtained in spleen, stomach and lung. The depression of hepatic GSH was found not to be a consequence of morphine-induced hypoxia or hypothermia, and could not be attributed to intracellular oxidation of GSH.

Animals↗

PubMed1988

An assay for phentolamine using high performance liquid chromatography with electrochemical detection.

A new method is presented for the detection of phentolamine by high performance liquid chromatography with electrochemical detection. The electrochemical detector was used in the oxidative mode at +900 mV potential versus Ag/AgCl reference. The on-column detection limit for phentolamine using this method was 3 ng, and detector response was linear for 3-1000 ng injected on column. The coefficient of variation for replicate injections was 2.4%. The measurement of phentolamine in biological samples was accomplished using yohimbime as the internal standard; retention time for yohimbine was 3.0 min while phentolamine eluted at 4.75 min. Biological samples were buffered to pH 9.2 and extracted with diethyl ether, followed by back extraction into 0.1 N HCl. The extraction efficiency for this method was 99.4% for phentolamine in serum and 59.3% in liver tissue. The detection limit for phentolamine was 5 ng/ml for 1.0-ml serum samples, and was 10 ng/ml for 1.0-ml liver homogenate samples. The disappearance of phentolamine from serum and liver after administration of a single ip dose of phentolamine to mice was determined using this method. Absorption from the ip route was rapid, with peak phentolamine concentrations achieved in 15 min or less. The elimination half-life of phentolamine in serum was approximately 50 min and was paralleled by disappearance of phentolamine in the liver.

Animals↗

PubMed1988

Effects of piperonyl butoxide on halothane hepatotoxicity and metabolism in the hyperthyroid rat.

A series of experiments were conducted to examine the potential role of phase I metabolism in halothane-induced liver injury in the hyperthyroid rat. The metabolism of halothane was determined in both hyperthyroid (triiodothyronine, 3 mg/kg per day, for 6 days) and euthyroid rats and in animals pre-treated with the cytochrome P-450 inhibitor piperonyl butoxide (75-100 mg/kg, i.p.). It was found that the hyperthyroid state, which is associated with a substantial increase in sensitivity to the hepatotoxic effects of halothane, decreases both oxidative and reductive routes of halothane metabolism in the rat. The production of trifluoroacetic acid (TFA), an oxidative metabolite, as well as that of chlorodifluoroethylene (CDF) and chlorotrifluoroethane (CTF), 2 reductive metabolites, was significantly reduced in hyperthyroid animals. Consistent with these findings serum and urinary bromide levels resulting from the formation of TFA, CDF or CTF were significantly reduced. The only route of halothane metabolism significantly increased by the hyperthyroid condition was the defluorination of halothane. Piperonyl butoxide administration did not render euthyroid animals sensitive to the halothane-induced hepatotoxicity and had no effect on the defluorination of halothane in euthyroid animals. However, piperonyl butoxide markedly increased the hepatotoxicity of halothane in hyperthyroid rats and, except for a modest increase in debromination reactions, decreased all measured indices of halothane metabolism including the defluorination of halothane. Thus, none of the observed changes in halothane metabolism produced by triiodothyronine or piperonyl butoxide treatment could be consistently correlated to the increases in hepatotoxicity linked to these 2 treatments. Based on these studies we suggest that the halothane hepatotoxicity induced in the hyperthyroid rat results from effects produced by either the parent compound or an as yet unidentified metabolite. In addition, these studies further demonstrate that considerable mechanistic differences exist for halothane-induced hepatotoxicity when comparing euthyroid and hyperthyroid animal models.

Administration, Inhalation↗

PubMed1988

Centrally mediated opioid induced depression of hepatic glutathione: effects of intracerebroventricular administration of mu, kappa, sigma and delta agonists.

It has recently been demonstrated that morphine produces a loss of hepatocellular glutathione in mice by virtue of its action within the central nervous system. The ability of opioid receptor antagonists to abolish morphine's effect on hepatic glutathione suggests that this action is opioid-receptor mediated. The involvement of opioid receptors in this phenomenon is confirmed in the present study in mice by the ability of naltrexone, 100 micrograms administered intracerebroventricularly (i.c.v.), to completely block the decrease in hepatic glutathione induced by an i.c.v. injection of 100 micrograms of morphine. Intracerebroventricular administration of the selective mu (mu) opioid receptor agonist, (D-Ala2,N-MePhe4,Gly-ol5)enkephalin (DAGO; 25-50 micrograms), or the selective delta (delta) opioid agonist, [D-Pen2,D-Pen5]enkephalin (DPDPE; 3-50 micrograms), like morphine, produced significant decreases in hepatic glutathione 3 h after administration. The selective kappa (kappa) opioid receptor agonists, ethylketocyclazocine (1-30 micrograms) and trans-(+/-)3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide-methane sulfonate (U50 488; 10-300 micrograms), as well as the selective sigma (sigma) opioid agonists, phencyclidine (PCP; 50-300 micrograms) and N-allylnormetazocine (SKF 10,047; 1-30 micrograms), had no effect on the concentrations of glutathione in the liver. It appears from these data that stimulation of mu- or delta-, but not kappa- or sigma-opioid receptors within the central nervous system results in a loss of hepatocellular glutathione.

Animals↗

PubMed1988

Antagonism of bromobenzene-induced hepatotoxicity by the alpha-adrenergic blocking agents, phentolamine and idazoxan.

The coadministration of phentolamine, an alpha-adrenoreceptor antagonist, was found to be effective in antagonizing the hepatotoxicity produced by bromobenzene in B6C3F1 mice. Multiple doses of phentolamine, administered in dosages of 10 mg/kg, attenuated almost completely the acute lethality resulting from a 0.5 ml/kg dosage of bromobenzene. Consistent with this decline in lethality, the coadministration of phentolamine significantly altered the magnitude of hepatocellular necrosis, the elevation of serum alanine aminotransferase activity, and the glutathione depression normally produced by this dose of bromobenzene. These protective effects were not limited to phentolamine. Idazoxan, an adrenergic antagonist more specific for alpha 2-receptors, was equally effective in antagonizing the bromobenzene-induced hepatotoxicity. Measurements of serum catecholamine levels revealed that the administration of hepatotoxic doses of bromobenzene elevates serum epinephrine levels. Furthermore, the phentolamine antagonism of the bromobenzene hepatotoxicity could be correlated to elevated serum epinephrine levels in both a temporal and dose-dependent manner. Although the mechanism of the phentolamine antagonism remains to be established, one promising hypothesis involves its prevention of an epinephrine-mediated compromise in the glutathione-dependent detoxification of bromobenzene.

Adrenergic alpha-Antagonists↗

PubMed1988

Antagonism of bromobenzene-induced hepatotoxicity by phentolamine: evidence for a metabolism-independent intervention.

A previous study has revealed that phentolamine markedly antagonizes the bromobenzene-induced hepatotoxicity and lethality in B6C3F1 mice. One potential mechanism by which phentolamine may diminish the bromobenzene-induced hepatotoxicity is by a direct or indirect interference with the metabolism of bromobenzene to toxic metabolites. In the present study, phentolamine cotreatment failed to alter the elimination of bromobenzene from serum or the distribution of bromobenzene to liver. This suggests that phentolamine cotreatment does not indirectly interfere with bromobenzene bioactivation secondary to changes in bromobenzene absorption, distribution, or elimination. Further, a phentolamine concentration 10- to 20-fold greater than those measured in vivo failed to alter the in vitro metabolism of bromobenzene to its ortho- and para-phenolic metabolites. It is believed that para-bromophenol represents the rearrangement product of the hepatotoxic 3,4-epoxide and that ortho-bromophenol is a product of the nonhepatotoxic 2,3-epoxide pathway. Thus, it appears that phentolamine does not antagonize bromobenzene-induced hepatotoxicity by inhibiting the formation of hepatotoxic intermediates, nor by enhancing metabolism via the nonhepatotoxic pathway. On the basis of these studies, we conclude that phentolamine antagonism of bromobenzene-induced hepatotoxicity occurs through a mechanism independent of bromobenzene bioactivation.

Adrenergic alpha-Antagonists↗

PubMed1988

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.

Animals↗

PubMed1987

A centrally-mediated effect of morphine to diminish hepatocellular glutathione.

Morphine administration has been associated with a decrease in hepatic glutathione (GSH) and an increase in the hepatotoxicity of compounds dependent upon GSH for detoxification. In this study, intraperitoneal administration of 100 mg/kg morphine in mice resulted in approximately a 25% decrease in hepatic GSH. The same magnitude of GSH depletion was also observed following intracerebroventricular (i.c.v.) injection of 100 micrograms of morphine, but no effect was observed when 100 micrograms of morphine was administered intravenously. Pretreating animals with either yohimbine (5 mg/kg, i.p.) or prazosin (5 mg/kg, i.p.) resulted in a partial blockade of i.c.v. morphine-induced change in hepatic glutathione concentrations. Adrenalectomy prior to i.c.v. morphine treatment completely prevented morphine-induced changes in hepatic GSH concentrations; however, the morphine response was restored in adrenalectomized mice supplemented with hydrocortisone (2.5 mg/kg). No effect on the ability of i.c.v. morphine to diminish GSH concentrations in the liver was observed following pretreatment with either propranolol (20 mg/kg, i.p.), atropine (1 mg/kg, i.p.), hexamethonium (15 mg/kg, s.c.), or destruction of peripheral adrenergic nerve terminals with 6-hydroxydopamine (30 mg/kg, i.p.). It is concluded that hepatocellular GSH concentrations may be diminished as a consequence of a central action of morphine. The response by liver GSH to this action does not appear to be mediated through adrenal medullary release of catecholamines or by autonomic stimulation of the liver. While corticosteroids are a necessary component of this response, their role is probably permissive. The ability of both prazosin and yohimbine to antagonize the effect of i.c.v. morphine on hepatic GSH, coupled with the apparent absence of a peripheral catecholaminergic mechanism, suggests that the adrenergic interaction with the i.c.v. morphine effect is also of central origin. Thus, the results of this study show that the central effects of morphine can result in a decrease in hepatic GSH, and that this effect is not mediated by a peripheral catecholaminergic mechanism.

Adrenalectomy↗

PubMed1987

Histamine and hepatic glutathione in the mouse.

A number of histamine receptor agonists and antagonists were utilized to study the effects of histamine on hepatocellular reduced glutathione (GSH) concentrations and the potential role of histamine as a mediator of morphine-induced hepatic GSH depression. Administration of histamine, the H1-histamine receptor agonist thiazolylethylamine, the H2-histamine receptor agonist impromidine, or the histamine-releasing substance compound 48/80 resulted in no significant change in hepatic GSH concentrations. The H1-histamine receptor antagonist chlorpheniramine and the H2-histamine receptor antagonist ranitidine were also without significant effect on hepatic GSH and did not antagonize morphine-induced GSH depression. These observations indicate that histamine release following morphine administration does not play a significant role in the subsequent depletion of hepatic GSH.

Animals↗

PubMed1987

Antagonism of cocaine-induced hepatotoxicity by the alpha adrenergic antagonists phentolamine and yohimbine.

The ability of the alpha adrenoreceptor antagonists phentolamine and yohimbine to antagonize cocaine-induced hepatotoxicity was determined in phenobarbital-induced B6C3/F1 mice. Hepatotoxicity was assessed by the histologic extent of necrosis, incidence of latent lethality and increases in serum alanine aminotransferase activity. The depression of hepatic glutathione levels also were measured. The administration of a single 5-mg/kg dose of phentolamine antagonized the decrease in glutathione levels and the elevation of aminotransferase activity caused by a 60-mg/kg dose of cocaine. Similar results were obtained in mice pretreated with the alpha-2 antagonist yohimbine. Whereas the duration of antagonism could be extended by administering a 30-mg/kg dose of yohimbine, the magnitude of the antagonism was not increased. In contrast to the experiments with the larger dose, multiple hourly doses of 2.5 mg/kg of yohimbine increased both the duration of antagonism and the magnitude of protection against the hepatotoxicity produced by cocaine. Yohimbine pretreatment reduced cocaine-induced latent lethality by 50%, but did not alter the time to lethality. The results of these experiments indicate that the alpha adrenoreceptor antagonist reduces the toxicity of cocaine rather than merely delaying its time of onset. This effect does not appear to result from an inhibition of the toxic metabolite(s) of cocaine, as a 10-fold molar excess of yohimbine failed to antagonize lipid peroxidation caused by in vitro incubation of cocaine with hepatic microsomes. Additional experiments in mice whose liver metabolism had not been induced by prior pretreatment with phenobarbital revealed that 60 mg/kg of cocaine lowered glutathione but was not hepatotoxic.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗