Single injections of epinephrine significantly lowered the hepatocellular levels of reduced glutathione (GSH) while producing small but significant elevations in serum glutamic-pyruvic transaminase (SGPT) activity. Hormones, i.e. glucagon and the corticosteroids, were also found to depress significantly hepatic glutathione. Based upon the agonist-antagonist studies performed, the hepatic GSH lowering effects of epinephrine appear to be mediated solely by alpha 2 receptors. Adrenergic antagonists with alpha 2 receptor blocking properties, phenotolamine and yohimbine, prevented the epinephrine-induced lowering of GSH while agonists with alpha 2 activity, clonidine and guanabenz, mimicked epinephrine's response. Antagonists with either alpha 1 or beta activity, i.e. prazosin, phenoxybenzamine and propranolol, did not prevent the epinephrine-induced lowering of hepatic GSH. Contrary to these findings antagonists with either alpha or beta receptor blocking activity significantly reduced the epinephrine-induced elevations in SGPT activity. Thus, there was no apparent relationship between the elevation of SGPT activity and the reduction in hepatic glutathione levels. It is concluded that the therapeutic administration of these compounds, or physiologic responses to stress or pain, may exacerbate the hepatotoxicity of compounds detoxified by GSH or alter important glutathione-mediated hepatocellullar processes.

Adrenergic alpha-Agonists↗

PubMedDate not supplied

Modified nucleoside 5'-triphosphonates as a new type of antiviral agents.

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Animals↗

PubMedDate not supplied

Solid-phase synthesis of oligodeoxynucleotides containing 3'-S-phosphorothiolate linkages.

For the first time a fully automated procedure has been developed for the incorporation of a 3'-S-phosphorothiolate linkage into DNA, using phosphorothioamidite monomers. Coupling yields with either of the activators 5-ethylthiotetrazole or 4,5-dicyanoimidazole were in the range of 80-90%. Coupling yields were equally good when performed on either a 0.2 or 1 mumole reaction column, thus facilitating large scale synthesis.

Oligonucleotides↗

PubMedDate not supplied

Adrenergic modulation of hepatotoxicity.

Summaries of the interactions caused by altering adrenoreceptor activity in conjunction with the administration of selected hepatotoxicants are provided in Table 2 and Fig. 1. These hepatotoxicants can be divided into two groups, one whose toxicity is increased by adrenergic agonist drugs (group I) and the other whose toxicity is decreased by adrenergic antagonists (group II). Group I includes carbon tetrachloride, acetaminophen, and methylphenidate. Perhaps the most remarkable aspect these chemicals have in common is the striking potentiation that occurs with cotreatment with certain adrenergic agonist drugs. For each of these, cotreatment with the appropriate adrenergic agent can result in massive hepatocellular necrosis from an otherwise nontoxic dose. In terms of the specific adrenoreceptors involved and mechanisms of potentiation, however, they have little in common. Potentiation of carbon tetrachloride hepatotoxicity appears to be mediated by alpha(2)-adrenoceptor stimulation, acetaminophen is potentiated by alpha(1)-adrenoreceptor agonists, and methylphenidate responds to beta(2)-adrenoreceptor stimulation. Studies of the potentiation of carbon tetrachloride and acetaminophen agree that the timing of adrenergic stimulation relative to the hepatotoxicant dose is critically important to the interaction but markedly different for these two toxicants. Acetaminophen was potentiated only when the adrenergic drug was administered as a 3-h pretreatment. This is apparently a consequence of a mechanism of potentiation that involves adrenergic depression of hepatic glutathione content and a requirement that peak effects on glutathione of both the adrenergic agent and acetaminophen be coincident. The mechanism of potentiation of carbon tetrachloride hepatotoxicity is uncertain but clearly does not involve hepatic glutathione content. In contrast to acetaminophen, adrenergic effects must occur within a time window a few hours after the carbon tetrachloride dose for potentiation to occur. The importance of dose timing has not been evaluated for adrenergic potentiation of methylphenidate hepatotoxicity, but it is clear that this interaction is based on yet a third mechanism. While only three hepatotoxicants of the group I type have been examined in detail, the diversity of receptor types and mechanisms involved suggest that this phenomenon may be relevant for a wide variety of hepatotoxic drugs and chemicals. This interaction is also of interest because factors or events that lead to increased adrenergic stimulation are common in everyday life. Most over-the-counter cold and allergy preparations contain sympathomimetic drugs, and many prescription drugs produce adrenergic effects as either an extension of the intended therapeutic effect or as a side effect. Stress and some disease states can also lead to significant increases in peripheral adrenergic activity, creating the potential for increased susceptibility to hepatic injury from exposure to certain drugs or chemicals. Cocaine and bromobenzene represent group II, chemicals whose hepatotoxicity is diminished by cotreatment with adrenergic antagonist drugs. In the case of cocaine, adrenergic antagonist cotreatment was capable of reducing serum alanine aminotransferase activities by approximately 50%. For bromobenzene, the protection afforded by adrenergic antagonist cotreatment was more profound, with minimal hepatic lesions resulting from doses of bromobenzene that otherwise produced lethal hepatic necrosis. For the chemicals in group II, experimental observations are consistent with a phenomenon in which adrenergic potentiation of toxicity is supplied by the hepatotoxicant itself. Both cocaine and bromobenzene, in hepatotoxic doses increase endogenous catecholamine levels. When the effects of the elevated catecholamines are removed with the appropriate adrenergic antagonist, much lower toxicity (presumably due only to the direct hepatotoxic effects of the drug or chemical) is obse

Adrenergic alpha-Agonists↗

PubMedDate not supplied

Evaluation of morphine as compared to meperidine when administered to the moderately anxious pediatric dental patient.

This investigation evaluated two narcotic regimens used to sedate pediatric dental patients who previously demonstrated uncooperative behavior. One consisted of submucosal morphine (0.15 mg/kg), and the other, oral meperidine (2.2 mg/kg); both were administered in combination with oral promethazine (1.1 mg/kg). Patients 2-7 years old were sedated with one of the two regimens and videotaped during dental treatment. If sedation was successful, the child received the other regimen at the next appointment, resulting in a total of 42 sedations in 29 children. Later, patient behavior was rated blindly by two independent observers viewing tapes of specific events during dental treatment. Fourteen of 23 (61%) patients receiving morphine and 11 of 19 (58%) patients receiving meperidine were sedated successfully. Vital signs, including pulse, respirations, blood pressure, and oxygen saturation were monitored and remained stable for both groups. ANOVA for repeated measures showed no significant differences for any vital sign in either group across time. Wilcoxon's signed rank test revealed significant improvement for the patients successfully treated in both groups when presedation behavior was compared with behavior during the events of rubber dam application, operative, restorative treatment, and exit (meperidine, P < 0.005 and morphine, P < 0.001). Improvement also was seen in the meperidine group for the event of local anesthesia (P < 0.01). Chi-square analysis showed no statistically significant differences in effectiveness or safety between the two sedative regimens.

Administration, Buccal↗

PubMedDate not supplied

Determination of metabolically derived nitroprocainamide in the urine of procainamide-dosed humans and rats by liquid chromatography with electrochemical detection.

The N-oxidized metabolites of the antiarrhythmic procainamide have previously been implicated as inciting agents in the autoimmune condition drug-related lupus. Although much data have been collected with respect to the in vitro behavior of these metabolites, relatively little has been accomplished in vivo because of their extreme reactivity. The determination of nitroprocainamide (NPA), a stable decomposition product of the reactive hydroxylamine and nitroso species, in the urine of rats dosed with procainamide is reported here using the sensitive and selective method of HPLC with electrochemical detection. For orally and i.v.-dosed animals, up to microgram amounts of NPA were excreted over 24 hr from an initial dose of 66-100 mg procainamide/kg body weight. Also, the apparent elimination of microgram quantities of NPA in the urine specimens of 9 of 11 patients undergoing treatment with procainamide was observed. This suggests that N-oxidation of the aromatic ring of procainamide is occurring at sufficient levels to result in the formation of significant amounts of the reactive hydroxylamine and nitroso metabolites in vivo, and may have direct implications in the diverse and widespread symptomatology associated with procainamide-induced drug-related lupus.

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

Procainamide acetylation in strains of rat and mouse.

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Acecainide↗

PubMedDate not supplied

The formation of procainamide hydroxylamine by rat and human liver microsomes.

A method is described, using HPLC and electrochemical detection, which permits the direct quantitation of procainamide hydroxylamine. Procainamide hydroxylamine was formed from procainamide by hepatic microsomes from both rat and human, with rat microsomes showing higher apparent formation rates. The apparent Km for formation of procainamide hydroxylamine was 0.044 mM for rat liver microsomes, with an apparent Vmax of 2.81 nmol/min/mg of protein. Estimates of Km from three human microsomal samples were 6.29, 2.89, and 6.88 mM. Vmax estimates were 0.31, 0.74, and 0.74 nmol/min/mg of protein, respectively, roughly an order of magnitude less than that observed for the rat. Microsomal formation in both species was inhibited by boiling the microsomes, eliminating NADPH from the incubation system, by preincubation with SKF 525A, cimetidine, or n-octylamine, or by gassing the microsomal incubation mixture with carbon monoxide. These observations suggest that procainamide hydroxylamine formation is cytochrome P-450 mediated. Procainamide hydroxylamine could not be detected in the blood of rats treated with a single dose of procainamide, 100 mg/kg, po. One potential reason for the inability to detect this metabolite in blood is indicated by the rapid disappearance in vitro of procainamide hydroxylamine added to whole blood. Most of this disappearance appears to be due to an interaction with hemoglobin.

Adult↗

PubMedDate not supplied

Comparison of human and mouse liver microsomal metabolism of bromobenzene and chlorobenzene to 2- and 4-halophenols.

Bromobenzene is metabolized by hepatic microsomes to two different epoxide intermediates, which then rearrange to form either ortho- or para-bromophenol. A rapid and sensitive technique utilizing HPLC with electrochemical detection is presented for the quantitation of these primary bromobenzene metabolites. This analytical procedure allows selective quantitation of phenolic products of microsomal metabolism without prior extraction. Application of this assay method to the microsomal metabolism of bromobenzene and chlorobenzene revealed that three important differences exist between mice and humans regarding the metabolism of these compounds. First, human liver microsomes have a greater affinity for halobenzene biotransformation to the hepatotoxic 3,4-epoxide, as indicated by the approximately 2-fold lower Km values for para-halophenol production compared with mouse liver microsomes. Second, human liver microsomes produce the hepatotoxic metabolite at a 2-fold greater rate than mouse liver microsomes, relative to the microsomal cytochrome P-450 content. And third, human liver microsomes produce less of the nonhepatotoxic ortho-halophenol metabolites at Vmax resulting in an average ratio of the hepatotoxic: nonhepatotoxic metabolite production that is 3.5 times higher than the ratio for B6C3F1 mice. These results indicate humans preferentially metabolize halobenzenes through the hepatotoxic 3,4-epoxide pathway, suggesting that humans may be more susceptible than mice to halobenzene-induced hepatotoxicity.

Animals↗