Benzo[alpha]pyrene (B[a]P) is a product derived from incomplete combustion of organic material and is considered responsible for chemically-induced cancer in humans. In the present study, the levels of noradrenaline (NA), dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxytryptamine (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) were measured in the brains of female Wistar rats 6, 12, 24 and 96 h after a single dose of B[alpha]P (50 mg kg(-1) b.w., i.p.), and also after repeated administration of B[alpha]P (50 mg kg(-1) b.w., i.p., 2 x wk, 1 mo). The brain regions studied were the striatum, hypothalamus, midbrain and cortex. Catecholamines were measured using high performance liquid chromatography (HPLC) and electrochemical detection. Significant changes were observed in the striatum where NA, DA, DOPAC were decreased after 24 h and HVA was decreased after 6 h. In contrast, no major alterations occurred in 5-HT and 5- HIAA. In the hypothalamus, a significant decrease in NA was observed after 96 h. In the midbrain, the most important change observed was the decrease in NA after 24 h. A trend toward an increase in 5-HIAA was observed in the cortex after 6 h. The results demonstrate that B[alpha]P induces alterations in the dopaminergic and serotoninergic systems throughout the brain. These alterations may lead to behavioural and hormonal disturbances.
Disulfiram is used in the treatment of chronic alcoholism, because of the unpleasant symptoms it provokes after ethanol intake. The underlying mechanism is believed to be the accumulation of acetaldehyde in the blood, due to inhibition of the liver aldehyde dehydrogenases. In addition, it is known that disulfiram also has some neurotoxic properties. The aim of our study was to investigate the relationship between the pharmacological and neurotoxicological properties of disulfiram with respect to the doses applied. Increasing doses of disulfiram (25, 50, 75, 100 and 150 mg/kg) were administered intraperitoneally to Wistar rats and the hepatic enzyme activities of alcohol and aldehyde dehydrogenases were measured. Also, in two brain subregions (midbrain and hypothalamus) the levels of noradrenaline, dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid were determined. The higher dose of disulfiram (150 mg/kg) produced lethal effects in all treated animals. Aldehyde dehydrogenase activities were inhibited by disulfiram in a dose-dependent way, while alcohol dehydrogenase was not affected at all. Concerning the levels of brain biogenic amines, disulfiram produced a significant reduction in noradrenaline and an increase in dopamine levels in both structures of the brain, in a dose-dependent way. However, the lowest dose applied (25 mg/kg) had no effects on brain catecholamines. It is known that high doses of disulfiram may cause severe encephalopathy and peripheral neuropathy in humans, which could be attributed to the impairment of the metabolism of brain biogenic amines, due to inhibition of dopamine-b-hydroxylase. Our experimental data show that disulfiram affects the level of brain biogenic amines at dose levels higher than those inhibiting the activity of aldehyde dehydrogenase. Therefore, in clinical practice 'disulfiram reaction' could still be achieved with a low dosage regimen not producing neurotoxicity.
Disulfiram is used in the treatment of chronic alcoholism, because of the unpleasant symptoms it provokes after ethanol intake. The underlying mechanism is believed to be the accumulation of acetaldehyde in the blood, due to inhibition of the liver aldehyde dehydrogenases. In addition, it is known that disulfiram also has some neurotoxic properties. The aim of our study was to investigate the relationship between the pharmacological and neurotoxicological properties of disulfiram with respect to the doses applied. Increasing doses of disulfiram (25, 50, 75, 100 and 150 mg/kg) were administered intraperitoneally to Wistar rats and the hepatic enzyme activities of alcohol and aldehyde dehydrogenases were measured. Also, in two brain subregions (midbrain and hypothalamus) the levels of noradrenaline, dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid were determined. The higher dose of disulfiram (150 mg/kg) produced lethal effects in all treated animals. Aldehyde dehydrogenase activities were inhibited by disulfiram in a dose-dependent way, while alcohol dehydrogenase was not affected at all. Concerning the levels of brain biogenic amines, disulfiram produced a significant reduction in noradrenaline and an increase in dopamine levels in both structures of the brain, in a dose-dependent way. However, the lowest dose applied (25 mg/kg) had no effects on brain catecholamines. It is known that high doses of disulfiram may cause severe encephalopathy and peripheral neuropathy in humans, which could be attributed to the impairment of the metabolism of brain biogenic amines, due to inhibition of dopamine-beta-hydroxylase. Our experimental data show that disulfiram affects the level of brain biogenic amines at dose levels higher than those inhibiting the activity of aldehyde dehydrogenase. Therefore, in clinical practice 'disulfiram reaction' could still be achieved with a low dosage regimen not producing neurotoxicity
Aldehyde dehydrogenase (ALDH) is involved in the metabolism of endogenous and exogenous aldehydes originating from biogenic amines, lipids, food and drugs. Rat liver contains at least two cytosolic ALDHs that can be stimulated by inducers of drug metabolism. Phenobarbital- type inducers increase ALDH1 activity while polycyclic aromatic hydrocarbons (such as benzo[alpha]pyrene) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increase ALDH3c isoenzyme activity. Two rat substrains were isolated according to a different induction of hepatic ALDH after treatment with phenobarbital (PB). Animals that responded to treatment (RR) and those that did not respond (rr) were inbred and divided into two homogenous groups. These animals constituted an ideal experimental model due to their common origin. Apart from the dramatic induction of cytosolic ALDH1 and ALDH3c, the effects of PB on pentoxy-, ethoxy- and methoxy-resorufin-O-dealkylase (P-, E-, and MROD) between the two substrains were also studied. 3-Methylcholanthrene (3MC) greatly increased ALDH3c levels in both substrains, although it was slightly more pronounced in the rr rats, in which it was assessed either as ALDH3c or as total cytosolic ALDH. A similar trend was also noted in EROD, PROD and MROD activities. Dealkylation of the methoxy group was found to be statistically different between the two substrains (rr > RR). The relevance of the biochemical findings with the in vivo hepatic capacity for drug metabolism was investigated by measuring the duration of zoxazolamine paralysis. Both animal substrains were tested with zoxazolamine either without pretreatment or after administration of PB or 3MC: the paralysis produced by zoxazolamine lasted for a longer period in rr than in RR rats. After pretreatment with PB, the duration of paralysis was greatly reduced, but the differences between the two substrains remained. Pretreatment with various doses of 3MC produced differences in the duration of paralysis in RR and rr rats, although the time period was much shorter than that observed in control animals.
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