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PubMed2004

Detoxification of organophosphorus compounds by recombinant carboxylesterase from an insecticide-resistant mosquito and oxime-induced amplification of enzyme activity.

Currently, bioremediation is a promising approach to the degradation of environmental pollutants. Here we describe the application of the recombinant insecticide-resistant mosquito carboxylesterase B1 to detoxify organophosphorous compounds. However, this approach has a major limitation: 1:1 stoichiometry of the enzyme detoxification of those organophosphorous compounds containing no carboxyl ester bonds, such as paraoxon, chlorpyrifos etc. To improve the effectiveness of the enzymatic detoxification of organophosphorous compounds, we used a combination of carboxylesterase B1 with the uncharged oxime diacetylmonoxime. It was demonstrated that the repeated addition of 20 times the molar concentration of paraoxon to carboxylesterase B1 every 2 h in the presence of 4 mM diacetylmonoxime did not result in significant inhibition of the enzyme. The stoichiometry of enzyme detoxification was higher than 45:1 and 20:1 for paraoxon and chlorpyrifos, respectively. The kinetic experiments on reactivation of organophosphorus compound-inhibited carboxylesterase B1 showed that the half-life for paraoxon- and chlorpyrifos-inhibited carboxylesterase reactivation is 0.75 and 0.88 h, respectively. Using the recombinant insecticide-resistant mosquito carboxylesterase with oxime is an effective approach for detoxification of organophosphorous compounds.

Animals↗

PubMed1996

Cyanide detoxification in rats exposed to acetonitrile and fed a low protein diet.

Different neurological syndromes have been associated with exposure to cyanide. Dietary cyanide exposure from cassava roots combined with a low intake of the sulfur amino acids necessary for cyanide detoxification has been implicated in the causation of konzo, an upper motoneuron disease identified in Africa. We have investigated the effect of a low protein diet on the capacity for cyanide detoxification. Rats were fed normal chow containing 18% protein or a low protein diet with 5% protein. To expose rats to cyanide the drinking water was supplemented with 40 or 80 mM acetonitrile (CH3CN) for up to 4 weeks. Weight gain was monitored and 24-hr urines were collected for analyses of total sulfur, inorganic sulfate, thiocyanate, and 2-aminothiolazine-4-carboxylic acid (ATC). Blood was collected for analyses of cyanide and cyanate. Rats on a normal diet grew throughout the experiment, while those on a low protein diet initially lost weight and then stabilized at a constant weight. Rats exposed to acetonitrile all progressively lost weight, those on a low protein diet at the highest rate. Signs of neurological damage were not observed. Rats not exposed to acetonitrile excreted < 0.2% of sulfur as thiocyanate and those on a low protein diet reduced their total sulfur excretion to one-third that of rats of the normal diet. Rats on the normal diet did not change total sulfur excretion during exposure to acetonitrile, although thiocyanate now contributed more than two-thirds of excreted sulfur. Rats on a low protein diet exposed to acetonitrile increased both total sulfur and thiocyanate excretion to the levels of rats on a normal diet. Rats exposed to acetonitrile had manyfold increases of circulating concentrations of cyanide and cyanate and of urinary excretion of ATC. There was a positive correlation between blood cyanide concentrations and the plasma concentration of cyanate. It is concluded that the rat has a high capacity for detoxification of cyanide. During adaptation to a low protein intake, sulfur is conserved but cyanide detoxification is still possible at the cost of extensive protein catabolism. It is thus possible that subclinical cyanide exposure could interfere with normal growth and development. The observation of a relationship between circulating cyanide on the one hand and circulating cyanate and urinary excretion of ATC on the other highlights the possibility that cyanide metabolites may mediate neurotoxic effects of cyanide.

Acetonitriles↗

PubMed1998

The roles of CYP3A and CYP2B isoforms in hepatic bioactivation and detoxification of the pyrrolizidine alkaloid senecionine in sheep and hamsters.

The roles of cytochrome CYP3A and CYP2B isozymes in the bioactivation and detoxification of the pyrrolizidine alkaloid (PA) senecionine (SN) have been investigated in vitro with sheep and hamster hepatic microsomes. Our results show that the rate of SN activation measured by (+/-)-6, 7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP) formation greatly exceeded the rate of SN N-oxide formation (detoxification) in hamsters. In contrast, SN N-oxide, a detoxification product, was the major metabolite in sheep with much lower DHP production. Immunoinhibition studies with anti-sheep CYP3A and CYP2B antibodies show that members of CYP3A subfamily play the major role in the conversion of PA to pyrrolic metabolites in both species (over 90% in sheep; 68% in hamster). These enzymes also contribute 38.8 and 41. 3% of SN N-oxidation in sheep and hamsters, respectively. In contrast, CYP2B isoforms have a limited capacity toward DHP formation in both species (47% in sheep; 32% in hamster), while these enzymes catalyzed only 24.6 and 35.4% SN N-oxidation in sheep and hamster, respectively. Using triacetyloleandomycin (TAO) and gestodene, two highly selective chemical inhibitors of CYP3A isoforms, our data show that 90% of DHP formation was inhibited by either inhibitor in sheep. Gestodene appeared to be more efficient than TAO in the inhibition of DHP production in hamsters. Testosterone 6beta-hydroxylase activity, a functional marker of CYP3A, was significantly inhibited by TAO and gestodene in sheep liver microsomes and by gestodene (100 microM) in hamster liver microsomes. These results suggest that CYP3A isozymes have important roles in bioactivation and detoxification of PA in both species, whereas CYP2B subfamily members are less efficient in biotransformation of PA.

Animals↗

PubMed1988

Hepatic detoxification and hepatic function in chronic active hepatitis with and without cirrhosis.

The detoxification capacity of the liver in chronic active hepatitis (CAH) without liver cirrhosis (LC) is not sufficiently known. Therefore, we examined, in 156 patients with morphologically proven CAH of different stages, plasma ammonia, free phenols, indican, glucuronic acid and urea synthesis rate as parameters for liver detoxification. We found a significant increase of ammonia, phenols, and indican and a significant decrease of glucuronic acid and urea synthesis rate parallel to the stage of CAH without LC. In 34 CAH patients with complete recovery, a retrospective 10-year follow-up was possible. Parallel to the normalization of liver morphology and general liver tests, detoxification parameters also normalized. However, the detoxification disorders in CAH without LC are mild in nature and do not produce hepatic encephalopathy. Probably, they are caused by a reduced synthesis of the urea-cycle enzymes and of glucuronyltransferase in the liver.

Ammonia↗

PubMed2001

[The "qualified outpatient detoxification" model project].

In 1998, a model project of outpatient detoxification in alcoholics was initiated in a German outpatient clinic. Inclusion and exclusion criteria of this project, which is supported by local health care providers, are presented. Between August 1998 and June 2000, 205 patients were screened. Psychotherapeutically motivating elements are integrated, so that this may be termed a "qualified" detoxification program. One hundred forty-one patients entered the program, of whom 127 (90%) successfully finished treatment. No serious medical complications were observed. Of those who completed treatment, 121 entered further alcoholic rehabilitation programs. Some preliminary data of an ongoing catamnestic study suggest that, after a mean of 10 months post-detoxification, 61 (50%) of these patients are still abstinent and in rehabilitation programs. The findings suggest that outpatient alcohol detoxification is safe and efficient, at least for a subgroup of patients, and also indicate the possible efficacy of concomitant psychotherapeutic interventions during this mode of treatment.

Adult↗

PubMed1999

High protein diet induces pericentral glutamate dehydrogenase and ornithine aminotransferase to provide sufficient glutamate for pericentral detoxification of ammonia in rat liver lobules.

The liver plays a central role in nitrogen metabolism. Nitrogen enters the liver as free ammonia and as amino acids of which glutamine and alanine are the most important precursors. Detoxification of ammonia to urea involves deamination and transamination. By applying quantitative in situ hybridization, we found that mRNA levels of the enzymes involved are mainly expressed in periportal zones of liver lobules. Free ammonia, that is not converted periportally, is efficiently detoxified in the small rim of hepatocytes around the central veins by glutamine synthetase preventing it from entering the systemic circulation. Detoxification of ammonia by glutamine synthetase may be limited due to a shortage of glutamate when the nitrogen load is high. Adaptations in metabolism that prevent release of toxic ammonia from the liver were studied in rats that were fed diets with different amounts of protein, thereby varying the nitrogen load of the liver. We observed that mRNA levels of periportal deaminating and transaminating enzymes increased with the protein content in the diet. Similarly, mRNA levels of pericentral glutamate dehydrogenase and ornithine aminotransferase, the main producers of glutamate in this zone, and pericentral glutamine synthetase all increased with increasing protein levels in the diet. On the basis of these changes in mRNA levels, we conclude that: (a) glutamate is produced pericentrally in sufficient amounts to allow ammonia detoxification by glutamine synthetase and (b) in addition to the catalytic role of ornithine in the periportally localized ornithine cycle, pericentral ornithine degradation provides glutamate for ammonia detoxification.

Ammonia↗

PubMed2006

Clinical characteristics and service utilization patterns of clients with schizophrenia-spectrum disorders in public residential detoxification settings.

Little is known about the treatment needs of clients found in residential detoxification programs who have comorbid schizophrenia-spectrum and substance use disorders. This study (N = 166) compares the service use patterns of comorbid detoxification clients with schizophrenia-spectrum disorders (CDT-S) to two other client groups: (1) comorbid detoxification clients with other mental health disorders (CDT-O), and (2) comorbid clients in residential mental health facilities with schizophrenia-spectrum disorders (CMH-S). Results show that CDT-S clients were much less likely to receive subsequent mental health treatment than CMH-S clients. Findings indicate that detoxification programs may be important settings in which to identify clients with schizophrenia who have unmet mental health treatment needs.

Adult↗

PubMed2006

The detoxification limitation hypothesis: where did it come from and where is it going?

The detoxification limitation hypothesis is firmly entrenched in the literature to explain various aspects of the interaction between herbivores and plant toxins. These include explanations for the existence of specialist and generalist herbivores and for the prevalence of each of these. The hypothesis suggests that the ability of mammalian herbivores to eliminate plant secondary metabolites (PSMs) largely determines which plants, and how much, they can eat. The value of the hypothesis is that it provides a clear framework for understanding how plant toxins might limit diet breadth. Thus, it is surprising, given its popularity, that there are few studies that provide experimental support either for or against the detoxification limitation hypothesis. There are two likely reasons for this. First, Freeland and Janzen did not formally propose the hypothesis, although it is implicit in their paper. Second, it is a difficult hypothesis to test, requiring an understanding of the metabolic pathways that lead to toxin elimination. Recent attempts to test the hypothesis appear promising. Results suggest that herbivores can recognize mounting saturation of a detoxification pathway and adjust their feeding accordingly to avoid intoxication. One strategy they use is to ingest a food containing a toxin that is metabolized by a different pathway. This demonstrates that careful selection of food plants is a key to existing in a chemically complex environment. As more studies characterize the detoxification products of PSMs, we will better understand how widespread this phenomenon is.

Food Preferences↗

PubMed2007

Zea mays: benzoxazolinone detoxification under sulfur deficiency conditions--a complex allelopathic alliance including endophytic Fusarium verticillioides.

Benzoxazolinone detoxification is similar in plants grown under sulfur deficiency conditions and in control plants grown with an optimal S supply. However, when S-deficient plants were treated with metolachlor before benzoxazolin-2(3H)-one (BOA) incubation, detoxification was reduced, as indicated by a lower accumulation of the detoxification products BOA-6-O-glucoside and glucoside carbamate and by a loss of BOA-6-OH glucosyltransfease activity. Root colonizing microorganisms and the endophytic fungus Fusarium verticillioides participated in benzoxazolinone detoxification by converting the compound to 2-acetamidophenol (AAP) or O-hydroxyphenyl malonamic acid (OHPMA), a process accompanied by the appearance of phenoxazinone. Maize roots, however, absorbed AAP and OHPMA only in traces. Absorbed traces of OHPMA stimulated maize radicle growth, and traces of AAP stimulated cress. Phenoxazinone inhibited the growth of cress radicles at concentrations higher than 500 microM, whereas maize radicles were hardly affected. F. verticillioides did not convert benzoxazolinone to any known microbial degradation product when the medium of maize seedlings was inoculated with the fungus under sterile condition. Plant-fungus interactions seem to be important in plant survival of allelopathic attacks. This study points to a complicated network of allelopathic interactions that are influenced by biotic and abiotic factors, including herbicides.

Acetamides↗

PubMed1996

In vivo detoxification of cyanide by cystathionase gamma-lyase.

The results of several in vitro studies have suggested that the enzyme cystathionase gamma-lyase (EC 4.4.1.1) may function in the endogenous detoxification of cyanide; however, this possibility has not been investigated in vivo. If cystathionase gamma-lyase in involved in the endogenous detoxification of cyanide, it logically follows that inhibiting cystathionase gamma-lyase should increase the toxicity of cyanide. To test this hypothesis, the activity of cystathionase gamma-lyase was inhibited with a suicide inhibitor, 2-amino-4-pentynoic acid (propargyl-glycine). The activity of liver cystathionase gamma-lyase activity was decreased 96.8% by administration of propargylglycine, indicating that the propargylglycine treatment was effective. The propargylglycine treatment did not alter the activity of thiosulfate:cyanide sulfurtransferase (EC 2.8.1.1) or 3-mercaptopyruvate:cyanide sulfurtransferase (EC 2.8.1.2), two other enzymes that have been proposed to be involved in the detoxification of cyanide. The LD50 of cyanide in rats treated with propargylglycine was 5.14 +/- 0.029 mg NaCN/kg, which was significantly (P < 0.05) lower than the 5.98 +/- 0.008 mg NaCN/kg LD50 of cyanide determined in control rats. The results of these studies suggest that cystathionase gamma-lyase may participate in the detoxification of cyanide in vivo.

Animals↗

PubMed1995

P450 enzyme CYP2B catalyzes the detoxification of diisopropyl fluorophosphate.

Phenobarbital and some other enzyme-inducers are known to reduce organophosphate toxicity. One suggested mechanism is the induction of liver cytochrome P450 enzymes catalyzing monooxygenation reactions. The aim of the present study was to elucidate the cytochrome P450 subfamily, or P450 isoenzyme(s), participating in the detoxification of diisopropyl fluorophosphate (DFP) in the rat. DFP resulted in a type I spectrum in liver microsomes from phenobarbital- or RP 52028-treated rats (binding constants 0.32 and 0.17 microM, respectively) and in a purified P450 preparation enriched with CYP2B. The spectrum was reversible by metyrapone, an inhibitor of the CYP2B enzyme subfamily. The 7-pentoxyresorufin O-dealkylase activity was inhibited by DFP in liver microsomes from phenobarbital- or RP 52028-treated rats and in a reconstituted system containing the purified CYP2B preparation. In microsomes from phenobarbital-pretreated rats, the inhibition was of a mixed type, i.e., competitive-non-competitive (Km = 0.5 microM; Ki = 6 microM). The microsomal fractions of livers from phenobarbital- or RP 52028-treated rats detoxified DFP effectively in vitro, as measured by a decrease in the DFP inhibition of cholinesterase activity. This detoxification was antagonized by metyrapone and by an antibody raised against purified CYP2B preparation. Clotrimazole, an inhibitor of P450 enzymes, inhibited the detoxification of DFP in rat liver in vivo. A genetically-modified hamster cell line expressing CYP2B1 oxidized NADPH in the presence of DFP. No such oxidation was detected in the parent cell line. These studies suggest that CYP2B1 metabolizes DFP and may significantly contribute to the detoxification of this organophosphate in vivo.

Animals↗

PubMed1996

The effect of formaldehyde, hydrogen peroxide and genetic detoxification of pertussis toxin on epitope recognition by murine monoclonal antibodies.

The effect of detoxification of pertussis toxin (PT) for vaccine usage by either genetic manipulation, hydrogen peroxide or formaldehyde treatment on epitope recognition by a large collection of murine monoclonal pertussis toxin antibodies (PT MAbs) was assessed in a solid-phase and a soluble phase enzyme-linked immunosorbent assay (ELISA). The MAb binding patterns were found to be different in the two assays as the immobilization step appeared to cause conformational alterations in the native as well as the toxoided forms of PT. According to the solid-phase ELISA, genetic, hydrogen peroxide and 0.35% formaldehyde detoxification of PT resulted in reduced epitope binding in 2.9, 31.4 and 78.1% of the MAbs, respectively. In the soluble-phase ELISA, in which the MAbs were allowed to react with the toxoids or native toxin in solution, the percentages of MAbs showing decreased binding activity were 9.1, 50.0 and 71.4%, respectively. Stabilization of native PT and the genetically inactivated PT by 0.035% formaldehyde reduced the epitope binding activity in 50.0 and 8.7% of the MAbs, respectively. Increased antibody binding in the soluble-phase ELISA was observed in some of the toxoids: this ranged from 0% in the 0.35% formaldehyde-treated PT to 13.6% in the hydrogen peroxide-treated and 27.3% in the genetically detoxified PT. Regarding the effects of detoxification on epitopes recognized by PT-neutralizing MAbs in the soluble-phase ELISA, we found that treatment of PT with either 0.035%, 0.35% formaldehyde or hydrogen peroxide induced impairment of epitope binding in 72.7, 81.8 and 45.5% of the MAbs, respectively. In the genetically inactivated PT, the epitopes recognized by the neutralizing MAbs either appeared to remain intact or to show increased MAb binding activity. The epitope-binding patterns of several PT MAbs with mouse-protective properties varied considerably and were shown to be dependent on the detoxification procedure employed. The relevance of epitope alterations on PT as a vaccine component is discussed. The results of the present study may have important implications for future quality assessment of PT for use in acellular pertussis vaccines.

Animals↗

PubMed1996

Metabolism and detoxification of nitrite by trout hepatocytes.

Nitrite (NO2-) is one of the most important toxicants to fish. Freshwater fish are especially sensitive, particularly salmonids. Nitrite uptake is thought to occur via the HCO3-, Cl- -exchanger at the gill epithelia with nitrite substituting for chloride. In this way freshwater fish accumulate nitrite in the blood up to 100-fold from the surrounding water. Another source, endogenous nitrite as a degradation product of nitric oxide, rarely leads to pharmacologically relevant concentrations. We developed a new method for the determination of nitrate (NO3-) in biological samples and used it to measure nitrite oxidation in isolated rainbow trout (Oncorhynchus mykiss) hepatocytes which were found to detoxify nitrite to the almost non-toxic nitrate. Detoxification is inhibited by 0.05 mM bumetanide and 0.1 mM furosemide but not by SITS and DITS, suggesting the involvement of the Na+, K+, 2Cl- -cotransporter with nitrite or nitrate substituting for chloride. Oxidation of nitrite is strongly accelerated by 0.05 mM uric acid. The efficacy of this antioxidant suggests that similar reactions are involved as known for haemoglobin [33]. However, in the case of trout liver also membrane bound detoxificating activity can be observed which is also enhanced by uric acid. ATP concentrations remained constant in the hepatocytes during all experiments demonstrating that hepatocyte energy status was not influenced by nitrite oxidation. Thus nitrite resistance in fish is governed by at least two mechanisms, nitrite uptake and the rate of detoxification. It is unknown whether fish actually differ in their ability to distinguish between chloride and nitrite during branchial uptake, but evidence presented in this paper suggests a significant contribution of detoxification pathways to a possible nitrite tolerance of fish.

Animals↗

PubMed1982

Heroin addict responses to six weeks of detoxification with LAAM.

This paper describes the range of experience of 28 heroin addicts who received LAAM instead of methadone over six weeks in an outpatient detoxification program. Four patients are singled out to illustrate the variety of response during withdrawal, temporary abstinence from drugs, and social adjustment. The paper explores the motivation of patients and both their physical and subjective responses to the detoxification attempt. By describing a variety of patients, the paper documents clinical responses that cannot be communicated in statistical summaries or single-case reports. Overall, the cases illustrate the difficulties of brief-stay outpatient detoxification from heroin. Clinicians should expect to see only small steps toward rehabilitation during a patient's attempt to taper from opiates, but even minimal progress may justify the use of detoxification programs as a link between "street life" and the decision to enter long-term treatment.

Adult↗

PubMed1983

Treatment outcome in methadone detoxification: relationship to initial levels of illicit opiate use.

Two groups each of 10 patients enrolled in a 90-day outpatient detoxification program were classified on the basis of high (92.5% of tests) and low (7.5% of tests) rates of opiate-positive urine test results during two weeks of dosage stabilization. Pretreatment demographic variables did not differ between the two groups. Relapse to opiate use during the detoxification occurred in patients who were initially opiate free. By the end of the dose reduction period, opiate-positive rates were 60% and 87% of tests for the low and high opiate use groups, respectively. Sedative use and missed clinic days showed similar trends for both groups during the detoxification, although different patterns of drop-out from treatment were noted. Symptomatology increased during dose reduction for the low- but not for the high-frequency opiate group. In general, treatment outcome appeared equally poor for patients who showed low or high levels of illicit opiate drug use early in detoxification treatment.

Adult↗

PubMed1984

Breaking the 'detox-loop' for alcoholics with social detoxification.

A significant number of alcoholics do not respond to detoxification as a step on the way to rehabilitation. Instead, they periodically 'dry out' and subsequently return to alcohol abuse. They do not accept the responsibilities inherent in the sick role (cooperation in order to improve status of health by entering and continuing treatment), although they do accept the privileges (care, shelter and asylum). Repeated detoxifications (within medical and non-medical settings) of persons who do not commit themselves to entering rehabilitation, are of minimum benefit to the patient and absorb resources which could be better used by those more amendable to treatment. An appropriate level of care--social detoxification--should be provided for ' detox - loopers '. Such a model can focus on the alcoholic's social welfare needs. Social detoxification provides both respite and basic care. The door to ongoing rehabilitation through professional services, as well as self-help groups, can remain open, without being the main objective of the centre.

Alcoholism↗

PubMed1987

Neuropsychological performance in opiate addicts after rapid detoxification.

Neuropsychological performance before and after a rapid (1 week) detoxification treatment, was studied in heroin addicts. Ninety-three opioid dependents (DSM-III) were evaluated with a brief test battery assessing attention, memory and verbal fluency performance prior to their admission to a Detoxification Unit. Significant differences were noted between the addicts' performance and a group of 30 comparable normals, whose intellectual ability was similar. At re-evaluation addicts showed improvement in most measures, including general clinical status. Moreover, no differences between the sample of detoxificated addicts and controls on measures of neuropsychological performance were then detected. No relationship was found between psychopathological symptoms and neuropsychological functioning after the pharmacological detoxification of addicts. The length of addiction or drug consumption were not predictive of neuropsychological impairment in the present sample of heroin addicts.

Adolescent↗

PubMed1989

The detoxification of high dose heroin addicts in Pakistan.

Treatment services in Pakistan have been swamped by the recent appearance and rapid growth of heroin abuse, and there is an urgent need to initiate and strengthen effective responses. This paper presents the results of an exercise in national monitoring of heroin detoxification services in Pakistan. The study also offers the first systematic description of the withdrawal response of heroin addicts dependent upon doses greatly in excess of those reported in developed countries. The trial was conducted at four major treatment centres and looks at three of the most widely used detoxification procedures in Pakistan (symptomatic treatment only, opium reduction plus symptomatic treatment and clonidine). Data are presented on 118 addicts receiving inpatient detoxification from heroin. The results indicate that all three detoxification methods reduced peak levels of withdrawal symptoms to acceptable levels, and that all produced a return to baseline levels of symptomatology within 10 days or less. The three most persistent symptoms were aches and pains, restlessness and insomnia. Several differences were found between treatments, notably with regard to the number of drugs required to modify the withdrawal response. The implications of these and other results are discussed.

Adolescent↗