摘要:

We have purified the major reduced glutathione (GSH) S-transferases from 3 apparently normal human livers: two obtained at surgery and one at autopsy. Purification was by sequential gel filtration, GSH-affinity chromatography, and chromatofocusing. All three livers exhibited the same two major transferase peaks from chromatofocusing at pH 9.0 and 8.7 (designated C1 and C2, respectively) and several (2–4) minor peaks. Another major form (designated A1) from two livers eluted from chromatofocusing at pH 5.4, whereas the major form from the third liver (designated N1) eluted near neutral (pH 6.8). The transferase from erythrocytes eluted at pH 4.6. Isoelectric focusing revealed that the true pi of Al was pH 7.1 indicating that Cl, C2 and Al are all cationic. In sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis, Cl, C2 and Al exhibited the same single subunit (25,000) whereas Nl was different (26,000). The erythrocyte enzyme had a smaller subunit (23,500). Urea/SDS-polyacrylamide gel electrophoresis resolved the apparent single subunit of Al, Cl and C2 into two distinct subunits. Cl from all 3 livers was a homodimer of the faster migrating subunit (designated subunit I); C2 was a heterodimer (designated I–II); and A1 was a homodimer of the slower migrating subunit (designated subunit II). Hybridization experiments demonstrated that by mixing C1 and A1 we could produce C2 whereas dissociation and reassociation of the subunits of C2 generated C1 and A1 as well as C2. Rabbit antiserum to C1 recognized C1 and C2, but not A1. Thus, the cationic human hepatic transferases are dimers of two distinct subun

ISSN:0031-7012    

DOI:10.1159/000138297

出版商:S. Karger AG    

年代:1987

数据来源: Karger

摘要:

Studies were performed on the response of hepatic xenobiotic metabolizing enzymes to in vitro and in vivo exposure to amrinone and milrinone, two new inotropic compounds used in congestive heart failure. Both drugs exerted selective effects on various cytochrome P-450-dependent metabolic activities as well as conjugating pathways. Aminopyrine N-demethylation was selectively inhibited by in vitro addition of milrinone but not amrinone, and laurate hydroxylation was inhibited by both drugs. Cytosolic glutathione-S-tranferase activity was profoundly inhibited by in vitro addition of both drugs. In vivo administration of either drug did not lead to significant inhibition of the pathways studied other than laurate hydroxylation which was depressed 20–30%. Irreversible binding of [14C]-amrinone-derived radioactivity to microsomal protein was partially NADPH-dependent. Inhibiton by SKF 525-A, α-naphthoflavone and various antioxidants was observed. No binding of [14C]-milrinone-derived radioactivity was seen. It is suggested that amrinone may selectively inhibit certain hepatic drug-metabolizing enzymes through metabolic electrophilic intermediat

ISSN:0031-7012    

DOI:10.1159/000138298

出版商:S. Karger AG    

年代:1987

数据来源: Karger

摘要:

Clearances of phenytoin (PHT), ethosuximide, and theophylline were estimated by a single-dose, single-sample strategy in healthy, young adult men and women. PHT concentrations were measured in salivary ultrafiltrates, ethosuximide concentrations were measured in saliva, and theophylline concentrations were measured in plasma. Estimates of the clearances of these three probes of hepatic drug-metabolizing enzymes revealed a trend toward slightly lower clearances among women compared to men: mean PHT clearance 15 % lower, ethosuximide clearance 27% lower, and theophylline clearance 14% lower. However, only differences in ethosuximide clearances were statistically significant. The use of oral contraceptive steroid (OCS) drugs on PHT and ethosuximide clearance was examined, and no significant effects were detected.

ISSN:0031-7012    

DOI:10.1159/000138299

出版商:S. Karger AG    

年代:1987

数据来源: Karger

摘要:

The mechanisms by which captopril inhibits vasopressin-stimulated osmotic water flow in the toad bladder have been investigated in vitro. Captopril has two possible mechanisms for the inhibitory action on the water flow, one is its stimulative effect on prostaglandin E2 (PGE2) biosynthesis by inhibition of kininase II activity, the other, is a direct effect on water flow independent of PGE2. Captopril inhibited the vasopressin-, cyclic adenosine monophosphate- and 3-isobutyl-1-methyl-xanthine-stimulated water flow. The inhibition of water flow by bradykinin was enhanced by captopril. These data indicate that captopril increased the amount of bradykinin in toad bladder cells resulting in the production of PGE2 which inhibited the increase in water flow induced by vasopressin. The inhibitory effect of captopril, however, also occurred in the presence of indomethacin, when the production of PGE2 was attenuated. Thus, it was concluded that captopril inhibits the vasopressin-stimulated water flow indirectly by inhibiting the degradation of bradykinin and thereby enhancing the production of PGE2, and directly at a site following the production of cyclic adenosine monophosphate by vasopressin.

ISSN:0031-7012    

DOI:10.1159/000138300

出版商:S. Karger AG    

年代:1987

数据来源: Karger

摘要:

In spontaneously breathing, lightly anesthetized rats with chronically implanted epicortical electrodes, tolerance times were measured from onset of progressive hypoxia, anoxia or decapitation, until ultimate apnea and subsequent cessation of brain electrical activities. Arterial and cerebrovenous blood was collected initially and during progressive hypoxia, starting 5 min after intravenous verapamil or NaCl (controls). Verapamil induced significant hyperpnea, arterial alkalosis, slight bradycardia and brain venous acidosis. During progressive hypoxia, hyperpnea persisted and heart rate remained stable for a longer period than in controls. Tolerance times were significantly prolonged. Time courses of arterial PO2 and PCO2 and of cerebrovenous PO2 were hardly influenced. However, arterial alkalosis and brain venous acidosis became highly significant versus control courses. This raised the O2 saturation in arterial and O2 extraction in cerebral venous blood. Sinus sagittalis puncture needle outflow (as a measure of CBF) tended to be below the control rat courses throughout. This led to a higher O2 supply to the brain in verapamil rats only during severe hypoxia. Verapamil did not prolong tolerance times in anoxia or ischemia. It is concluded that the verapamil-induced increase of tolerance to hypoxia is primarily due to the acid-base (Bohr) effects observed in response to hyperpnea and prolonged cerebral metabolic activity.

ISSN:0031-7012    

DOI:10.1159/000138301

出版商:S. Karger AG    

年代:1987

数据来源: Karger

摘要:

The stainless steel cannula inserting method was used to observe effects of nipradilol and prazosin on responses to periarterial electrical nerve stimulation and intraluminal administration of noradrenaline or phenylephrine in isolated and perfused canine mesenteric arteries. With small doses, nipradilol slightly potentiated vasoconstrictor responses to noradrenaline, but not periarterial stimulation. With a relatively large dose, nipradilol almost uniformly suppressed both periarterial stimulation-induced and noradrenaline- or phenylephrine-induced vasoconstriction. On the other hand, prazosin inhibited noradrenaline-induced vasoconstriction at small doses but not periarterial nerve stimulation-induced vasoconstrictions. At any doses, prazosin strongly inhibited noradrenaline-induced constrictions more markedly than periarterial stimulation-induced constrictions. It is concluded that nipradilol has a dominant inhibitory property on periarterial nerve stimulation-induced constriction in isolated canine mesenteric arteries.

ISSN:0031-7012    

DOI:10.1159/000138302

出版商:S. Karger AG    

年代:1987

数据来源: Karger