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Biomedical subjects

A A Badawy

Publications and source records attributed to A A Badawy.

At least 19 recordsLinked to original sources
PubMed1999

Tryptophan metabolism in alcoholism.

Studies of tryptophan (Trp) metabolism in relation to the serotonin status in alcoholism are of 2 types: (1) those related to the pharmacological effects of ethanol; (2) those concerning the serotonin status in the absence of alcohol intake. In experimental animals, acute and chronic ethanol administration and subsequent withdrawal exert a variety of effects on brain serotonin synthesis and turnover mediated by corresponding changes in Trp availability to the brain secondarily mainly to modulation of liver Trp pyrrolase (TP) activity. Alcohol-preferring mice and rats exhibit a central serotonin deficiency caused by, or in some cases associated with, a higher TP activity. Liver TP also appears to be a target of ethanol in man and evidence has recently emerged that alcoholics with positive family history are serotonin-deficient because of a lower availability of circulating Trp to the brain. Acutely, ethanol depletes brain serotonin in normal subjects, which may explain alcohol-induced aggression in susceptible individuals and also the incidence of depression in alcoholism. Trp availability to the brain is increased before the appearance of the alcohol-withdrawal syndrome in man, raising the possibility that the associated behavioural disturbances may involve the excitotoxic Trp metabolite quinolinate. Further studies of the Trp and serotonin status in relation to these important clinical features of alcohol dependence and alcoholism may therefore yield fruitful results.

Alcoholism↗
PubMed1999

Colchicine therapy for hepatic murine schistosomal fibrosis: image analysis and serological study.

Colchicine in a dose of 200 micrograms kg body weight/day (5 days/week) was administered to groups of Schistosoma mansoni infected mice 12 weeks post infection, either alone or following previous praziquantel therapy at the 8th week of infection. Certain groups received colchicine for 6 weeks and others received it for 10 weeks. Colchicine alone did not significantly change the light microscopic appearance of schistosomal liver fibrosis, or hepatic collagen content estimated histomorphometrically, and did not reduce the elevated IL-2 serum level. Colchicine induced hepatic injury consisted of intense inflammatory reaction in granuloma and portal tracts, hepatocytic degeneration, and elevation of serum AST and ALT levels. Colchicine seemed to postpone granulomatous reaction healing and collagen deposition rather than inhibiting collagen formation or degrading it. Colchicine inhibited proliferation of hepatocytes of infected mice by expanding G2-M phases of cell cycle, thus reduced Ag NOR count and raised cell ploidy and cyclic AMP serum level. Subsidence of schistosomal infection by praziquantel prior to colchicine therapy greatly reduced inflammatory cellular reaction, significantly diminished hepatic collagen deposition and serum IL-2 level, minimized the elevated nuclear ploidy and cyclic AMP serum level that followed colchicine therapy when administered alone.

Animals↗
PubMed1997

No early effects of electroconvulsive therapy on tryptophan metabolism and disposition in endogenous depression.

The possibility that a single electroconvulsive therapy (ECT) could increase tryptophan (Trp) availability to the brain for 5-hydroxytryptamine (5-HT, serotonin) synthesis was examined in 10 depressed patients before and during the 1st hour following an ECT and in 4 control (minor ear, nose, and throat surgical) subjects receiving similar premedication. Trp availability to the brain, expressed as the serum Trp: competing amino acid ratio, and related aspects of Trp disposition were not significantly altered by ECT any differently than from preoperative stress and premedication. We suggest that Trp availability to the brain and, hence, cerebral 5-HT synthesis are not altered in depressed patients early after a single ECT.

Adult↗
PubMed1996

Evaluation of colchicine with or without praziquantel therapy in the control of hepatic fibrosis in murine schistosomiasis.

Colchicine alone or following praziquantel was given to mice infected with Schistosoma mansoni either 6 or 10 weeks post infection. Praziquantel increased body weight gain, histologically reduced number, diameter and cellularity of granuloma and improved liver function parameters. Early praziquantel therapy decreased hepatic collagen content as detected by the colorimetric method and the serum procollagen propeptide (PIIIP), while later treatment at the 10th week of infection increased hepatic collagen content and serum PIIIP. Colchicine therapy significantly decreased body weight gain with significant weight loss after early treatment. Colchicine did not change the histologic picture of schistosomal liver fibrosis; it induced a detectable hepatocytic injury recorded ultrastructurally and histologically with excitation of the inflammatory reaction in the granuloma and in portal tracts after early treatment. Excess pigmentation in macrophages and Kupffer cells, binucleation and large sized hepatocytic nuclei were evident after colchicine therapy. Colchicine increased hepatic collagen content microgram/mg protein, raised globulin and total serum protein and normalized the raised serum PIIIP of infected mice, but had no effect on PIIIP of normal mice. Early cessation of schistosomal infection evidently minimized the adverse effects of colchicine.

Animals↗
PubMed1996

Tryptophan metabolism and disposition in relation to alcohol and alcoholism.

Tryptophan (Trp) metabolism and disposition in relation to alcohol and alcoholism are briefly reviewed. The changes observed could generally be classified into those: (1) exerted by acute or chronic alcohol administration and/or subsequent withdrawal; (2) already present in the absence of alcohol consumption, such as in naive alcohol-preferring animals or in abstinent alcoholics. In normal rats, acute ethanol administration activates liver Trp pyrrolase and exerts a biphasic effect on brain 5-HT (5-hydroxytryptamine or serotonin) synthesis, whereas chronic ethanol administration and subsequent withdrawal exert opposite effects on 5-HT synthesis mediated by corresponding changes in liver Trp pyrrolase activity. A cerebral 5-HT deficiency has been demonstrated in the alcohol-preferring C57BL mouse strain and in a number of alcohol-preferring rat lines, the mechanism of which is understood only in two models; the C57B1 mouse strain has a higher liver Trp pyrrolase activity and the P rat line from Indiana has a lower density of serotonergic fibres in cerebral cortex. In man, acute ethanol intake lowers circulating [Trp] and its availability to the brain, almost certainly by activating liver Trp pyrrolase. Some evidence exists for possible inhibition of pyrrolase activity in non-abstinent chronic alcoholics. Evidence in recently abstinent alcoholics suggests that Trp availability to the brain may be impaired and that this may be particularly so in patients with positive family history. Exploration of this latter possibility may be important in understanding the biological basis of predisposition to alcoholism.

5-Hydroxytryptophan↗
PubMed1996

Effects of chronic administration and subsequent withdrawal of ethanol-containing liquid diet on rat liver tryptophan pyrrolase and tryptophan metabolism.

An investigation of the effects of chronic administration of ethanol by the liquid diet procedure and its subsequent withdrawal on tryptophan (Trp) metabolism and disposition was performed in rats. Treatment with the control liquid diet caused an enhancement of liver Trp pyrrolase activity and mRNA abundance. These effects are not due to the starvation associated with this feeding procedure, because they occur in rats maintained on the liquid diet ad libitum. Chronic ethanol administration in the liquid diet did not further influence the above increased expression of Trp pyrrolase mRNA but caused inhibition of pyrrolase activity in competition with the effects of the diet. The control liquid diet decreased liver Trp concentration, but exerted no significant effects on other aspects of Trp disposition. The most striking and robust finding was a highly significant elevation in both Trp pyrrolase activity and mRNA expression at 7 h following discontinuation of ethanol availability, at which time there were demonstrable behavioural signs of ethanol withdrawal. The increase in Trp pyrrolase mRNA during alcohol withdrawal may be caused by corticosterone, whose circulating concentration was also increased. The changes in Trp pyrrolase activity during ethanol withdrawal were associated with significant alterations in Trp disposition including decreased brain Trp concentration and 5-hydroxytryptamine synthesis and turnover. These alterations may play a pivotal role in the behavioural manifestations of ethanol withdrawal including the hyperexcitement underlying audiogenic seizures. We suggest that rat Trp pyrrolase gene regulation may be an important biological determinant of the ethanol withdrawal syndrome and requires further study, and that the use of the liquid diet procedure in Trp metabolic studies requires inclusion of adequate controls and special attention to the effects of the liquid diet itself.

Alcohol Withdrawal Delirium↗
PubMed1996

Prevention by cycloheximide of the audiogenic seizures and tryptophan metabolic disturbances of ethanol withdrawal in rats.

Cycloheximide (20 mg/kg body wt, given intraperitoneally at-1 and 3 h after withdrawal of an ethanol-containing liquid diet) prevents the activation of liver tryptophan pyrrolase, the consequent inhibition of synthesis of brain 5-hydroxytryptamine, and the audiogenic seizures observed at 7 h after alcohol withdrawal. We suggest that a rapidly-turning-over protein mediates the alcohol withdrawal syndrome and discuss the possible role of liver tryptophan pyrrolase.

Acoustic Stimulation↗
PubMed1995

Decrease in circulating tryptophan availability to the brain after acute ethanol consumption by normal volunteers: implications for alcohol-induced aggressive behaviour and depression.

Acute ethanol consumption by fasting male volunteers decreases circulating trytophan (Trp) concentration and availability to the brain as determined by the ratio of (Trp) to the sum of its five competitors ([Trp]/[CAA]ratio). These effects of alcohol are specific to Trp, because levels of the 5 competitors are not increased. The decrease in circulating (Trp) is not associated with altered binding to albumin and may therefore be due to enhancement of hepatic Trp pyrrolase activity. It is suggested that, under these conditions brain serotonin synthesis is likely to be impaired and that, as a consequence, a possible strong depletion of brain serotonin in susceptible individuals may induce aggressive behaviour after alcohol consumption. The possible implications of these findings in the relationship between alcohol and depression are also briefly discussed.

Adult↗
PubMed1993

Tryptophan and 5-hydroxytryptamine metabolism in alcoholism.

Alcohol (ethanol) exerts a variety of effects on tryptophan (Trp) and 5-hydroxytryptamine (5-HT, serotonin) metabolism in man and experimental animals. In human healthy volunteers, acute ethanol consumption lowers circulating Trp availability to the brain, almost certainly leading to inhibition of cerebral 5-HT synthesis, possibly by enhancing liver Trp pyrrolase activity. In non-abstinent chronic alcoholics, however, Trp pyrrolase activity may be inhibited; here acute ethanol intake fails to lower circulating Trp concentration. Hepatic Trp degradation seems to be greater during abstinence, and chronic alcoholics then exhibit a decrease in Trp availability to the brain. It is, however, not clear whether this decrease and the likely associated higher liver Trp pyrrolase activity in abstinence are due to previous long-term alcohol consumption, or are inherent biological determinants of the low brain 5-HT in alcoholism. The latter possibility is supported by the recent implication of the Trp pyrrolase gene in alcoholism. In alcohol-preferring C57BL mice, the low brain [5-HT] is due to a higher liver Trp pyrrolase activity associated with a higher circulating [corticosterone]. Activity or expression of liver Trp pyrrolase and/or their induction by glucocorticoids may be important biological determinants of predisposition to alcohol consumption, and further work in this area may therefore be fruitful.

Alcoholism↗
PubMed1992

Effects of acute carbamazepine administration on haem metabolism in rat liver.

The effects of acute carbamazepine (CBZ) administration on haem metabolism in rat liver were examined in relation to the mechanism by which it exacerbates hepatic porphyrias. In a screening test for drug exacerbation of porphyria developed in this laboratory, CBZ at a very small dose (1.5 mg/kg, p.o.) behaved as an exacerbator, potentiating the loss of haem utilized by tryptophan pyrrolase (TP; tryptophan 2,3-dioxygenase; L-tryptophan-O2 oxido-reductase, decyclizing; EC 1.13.11.11) and the associated induction of activity of the rate-limiting enzyme of haem biosynthesis, 5-aminolaevulinate synthase (5-ALA-S) caused by the experimental porphyrogen 3,5-diethoxycarbonyl-1,4-dihydrocollidine. A larger dose of CBZ (50 mg/kg, i.p.) induced 5-ALA-S activity by 40-100% at 3 hr. This induction was preceded by an increase in the haem saturation of TP, and was abolished when such an increase was prevented by allopurinol. 5-ALA-S induction by CBZ was not associated with decreased turnover of the enzyme, nor with any significant changes in concentration of the major hepatic haemoprotein, cytochrome P450. It is suggested that CBZ may exacerbate the hepatic porphyrias by inducing 5-ALA-S activity secondarily to an increased utilization of haem by TP.

5-Aminolevulinate Synthetase↗
PubMed1991

The effects of lofepramine and desmethylimipramine on tryptophan metabolism and disposition in the rat.

Acute and chronic administration of lofepramine and its major metabolite desmethylimipramine (DMI) to rats elevates brain tryptophan concentration, thereby enhancing cerebral 5-hydroxytryptamine (5-HT) synthesis, by increasing the availability of circulating tryptophan to the brain, secondarily to inhibition of liver tryptophan pyrrolase (tryptophan 2,3-dioxygenase, L-tryptophan:O2 oxidoreductase, decyclizing; EC 1.13.11.11) activity. The pyrrolase inhibition by lofepramine occurs independently of metabolism to DMI, because it can be demonstrated directly in vitro. Lofepramine also differs from DMI in its action profile on the above and related aspects of tryptophan metabolism and disposition. These results demonstrate that lofepramine influences tryptophan and 5-HT metabolism and disposition independently of its major metabolite DMI, and are discussed briefly in relation to the mechanism of action of antidepressants.

Animals↗
PubMed1991

Effects of acute paroxetine administration on tryptophan metabolism and disposition in the rat.

1 The effects of acute oral administration of paroxetine on tryptophan metabolism and disposition were examined in the rat. 2 Basal liver tryptophan pyrrolase activity was inhibited by paroxetine in vitro and after oral administration. Maximum inhibition was caused by a 1 mg kg-1 dose. 3 Paroxetine administration also inhibited pyrrolase activity that had previously been enhanced by hormonal induction by cortisol or cofactor activation by haematin. The cortisol induction of the enzyme was, however, not inhibited by pretreatment of rats with paroxetine. 4 Paroxetine increased tryptophan availability to the brain, because of the above pyrrolase-inhibitory mechanism. Cerebral 5-hydroxytryptamine (5-HT) synthesis was accordingly enhanced, though this was apparent only with doses of the drug of up to 1 mg kg-1. With larger doses, decreased 5-HT turnover, probably as a result of 5-HT uptake inhibition, was the more dominant feature. 5 Paroxetine lowered circulating corticosterone concentration, but did not influence those of albumin, non-esterified fatty acids or glucose. 6 It is concluded that, in addition to inhibiting brain 5-HT turnover, paroxetine also, in common with 20 other antidepressants, enhances 5-HT synthesis by increasing brain tryptophan concentration secondarily to inhibition of liver tryptophan pyrrolase activity.

Administration, Oral↗
PubMed1989

Liver tryptophan pyrrolase. A major determinant of the lower brain 5-hydroxytryptamine concentration in alcohol-preferring C57BL mice.

The lower brain 5-hydroxytryptamine concentration in alcohol-preferring C57BL, compared with -non-preferring CBA, mice is caused by a decrease in circulating tryptophan availability to the brain secondarily to a higher liver tryptophan pyrrolase activity associated with a higher circulating corticosterone concentration. Activity or expression of liver tryptophan pyrrolase and/or their induction by glucocorticoids may be important biological determinants of predisposition to alcohol consumption.

Alcoholism↗
PubMed1989

Effects of acute ethanol administration on rat liver 5-aminolaevulinate synthase activity.

1. Liver 5-aminolaevulinate (ALA) synthase activity of 24 h-starved rats is maximally increased at 4 h after intraperitoneal administration of a 1.6 g/kg body wt. dose of ethanol. Larger doses cause a dose-dependent decrease in the extent of this stimulation, exhibiting a reciprocal relationship with an elevation of hepatic haem concentration, as suggested by the simultaneous increase in the haem saturation of tryptophan pyrrolase. 2. ALA synthase induction by ethanol is abolished if the above increase in pyrrolase saturation with haem is enhanced by theophylline, but is potentiated when the increase in the haem saturation is inhibited by anti-lipolytic agents. 3. ALA synthase induction by ethanol is also inhibited by inhibitors of alcohol dehydrogenase and aldehyde dehydrogenase. Acetaldehyde and acetate are, however, not responsible; they both decrease ALA synthase activity and increase the haem saturation of tryptophan pyrrolase. These latter effects of acetaldehyde are not mediated by acetate. 4. ALA synthase activity is also stimulated by succinate, which, however, also increases the haem saturation of tryptophan pyrrolase. 5. Ethanol does not influence the rate of ALA synthase degradation. 6. It is suggested that ethanol increases rat liver ALA synthase activity as a result of its own metabolism by the alcohol dehydrogenase-dependent pathway by a mechanism not involving decreased degradation of the former enzyme or the participation of the metabolites acetaldehyde and acetate.

5-Aminolevulinate Synthetase↗