The effect of chlorpromazine on the respiratory chain. Cytochrome oxidase

Dawkins, Massey; Judah, J. D.; Rees, K. R.

doi:10.1042/bj0720204

Cited by 67 publications

(37 citation statements)

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“…Berger (1957) found uncoupling of phosphorylation in liver, but not in brain mitochondria exposed to chlorpromazine. The precise site of uncoupling of the respiratory enzyme chain in the liver has been identified by Dawkins, Judah & Rees (1959), who also observed similar effects in the brain in the presence of 2 x 10-'M chlorpromazine. Chance (1959) has demonstrated that the controlling metabolite for coupled respiration is adenosine diphosphate (ADP) and thus in normal conditions the rate of aerobic energy production is limited by the concentration of ADP.…”

mentioning

confidence: 60%

“…It is necessary to use higher concentrations of chlorpromazine (2 x 10-4M) to detect uncoupling using direct measurements of the ratio of utilization of inorganic phosphate to oxygen uptake (Dawkins et al, 1959). Brain oxygen consumption in vitro is lower than that estimated in vivo, although brain slices (but not homogenates) can be made to respire at in vivo rates by electrical or cationic stimulation (McIlwain, 1953).…”

Section: Discussionmentioning

confidence: 99%

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THE EFFECT OF CHLORPROMAZINE ON ¹⁴C‐GLUCOSE METABOLISM IN MOUSE LIVER AND BRAIN

Skinner

Spector

1968

British Journal of Pharmacology and Chemotherapy

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Chlorpromazine in high concentrations decreases energy production in tissues in vitro by inhibiting cellular respiration and phosphorylation (Quastel, 1965). Berger (1957) found uncoupling of phosphorylation in liver, but not in brain mitochondria exposed to chlorpromazine. The precise site of uncoupling of the respiratory enzyme chain in the liver has been identified by Dawkins, Judah & Rees (1959), who also observed similar effects in the brain in the presence of 2 x 10-'M chlorpromazine. Chance (1959) has demonstrated that the controlling metabolite for coupled respiration is adenosine diphosphate (ADP) and thus in normal conditions the rate of aerobic energy production is limited by the concentration of ADP. Chance & Baltscheffsky (1958) have employed the concept of respiratory control ratio which is defined as the ratio of respiratory rate in the presence of added ADP to that rate obtained following its expenditure. The use of this measurement enables more sensitive detection of loosely coupled respiration than that obtained by direct P/O ratios.Administration of chlorpromazine to rats does not affect the oxygen uptake of homogenates of their tissues in vitro (Grenell, Mendelson & McElroy, 1955). In the presence of uncoupled respiration, however, impaired carbohydrate utilization can occur even though oxygen consumption is normal. This paper describes an investigation of the fate of [U-"C]-glucose in mice after the administration of chlorpromazine in order to detect alterations in energy dependent processes which would occur if significant respiratory uncoupling occurred in the intact animal. The ability of ADP to stimulate the respiration of brain and liver homogenates in the presence of chlorpromazine concentrations similar to those attained therapeutically has also been studied. METHODSSAS/ICI adult albino mice of either sex weighing 18-25 g were used.Tissue respirationOxygen uptake of tissue homogenates was measured manometrically at 37' C in a Warburg respirometer. Untreated mice were killed by cervical fracture and exsanguination. The brain and liver were rapidly removed and immediately plunged into ice-cold Hanks balanced salt solution. The tissues were then blotted, weighed on a torsion balance and homogenized in ice-cold Hanks EM

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confidence: 60%

Section: Discussionmentioning

confidence: 99%

THE EFFECT OF CHLORPROMAZINE ON ¹⁴C‐GLUCOSE METABOLISM IN MOUSE LIVER AND BRAIN

Skinner

Spector

1968

British Journal of Pharmacology and Chemotherapy

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“…Based on the role of MarR in regulating efflux pumps in E. coli, we tested the efflux pump inhibitors verapamil, chlorpromazine, and carbonyl cyanide 3-chlorophenyl hydrazone (CCCP) (30)(31)(32)(33). Verapamil and chlorpromazine compounds had modest potentiating effects on the MIC of MP-III-71 to wild-type H37Rv and complemented mutant 1; however, they did not alter the MIC of the resistant strain, mutant 1 (see Table S4 in the supplemental material).…”

Section: Resultsmentioning

confidence: 99%

Mutation of Rv2887 , a marR -Like Gene, Confers Mycobacterium tuberculosis Resistance to an Imidazopyridine-Based Agent

Winglee

Lun

Pieroni

et al. 2015

Antimicrob Agents Chemother

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Drug resistance is a major problem in Mycobacterium tuberculosis control, and it is critical to identify novel drug targets and new antimycobacterial compounds. We have previously identified an imidazo[1,2-a]pyridine-4-carbonitrile-based agent, MP-III-71, with strong activity against M. tuberculosis. In this study, we evaluated mechanisms of resistance to MP-III-71. We derived three independent M. tuberculosis mutants resistant to MP-III-71 and conducted whole-genome sequencing of these mutants. Loss-of-function mutations in Rv2887 were common to all three MP-III-71-resistant mutants, and we confirmed the role of Rv2887 as a gene required for MP-III-71 susceptibility using complementation. The Rv2887 protein was previously unannotated, but domain and homology analyses suggested it to be a transcriptional regulator in the MarR (multiple antibiotic resistance repressor) family, a group of proteins first identified in Escherichia coli to negatively regulate efflux pumps and other mechanisms of multidrug resistance. We found that two efflux pump inhibitors, verapamil and chlorpromazine, potentiate the action of MP-III-71 and that mutation of Rv2887 abrogates their activity. We also used transcriptome sequencing (RNA-seq) to identify genes which are differentially expressed in the presence and absence of a functional Rv2887 protein. We found that genes involved in benzoquinone and menaquinone biosynthesis were repressed by functional Rv2887. Thus, inactivating mutations of Rv2887, encoding a putative MarR-like transcriptional regulator, confer resistance to MP-III-71, an effective antimycobacterial compound that shows no cross-resistance to existing antituberculosis drugs. The mechanism of resistance of M. tuberculosis Rv2887 mutants may involve efflux pump upregulation and also drug methylation.T uberculosis (TB) is a devastating disease that infects one-third of the world's population and killed 1.5 million people in 2013 (1). TB is caused by Mycobacterium tuberculosis and is challenging and time-consuming to treat. Standard TB treatment is currently 6 months long and involves a 2-month intensive phase consisting of treatment with four antibiotics (isoniazid, rifampin, ethambutol, and pyrazinamide) followed by a 4-month continuation phase (treatment with isoniazid and rifampin only). However, despite this combination therapy, drug resistance is on the rise, and in 2013, there were an estimated 480,000 cases of multidrug-resistant (MDR) TB, which is defined as TB caused by bacteria that are resistant to at least isoniazid and rifampin. These cases require up to 2 years of treatment, but drug resistance is developing even under these conditions, and in 2014, 9% of MDR TB cases were extensively drug resistant (XDR), meaning that they were also resistant to isoniazid, rifampin, a fluoroquinolone, and an injectable anti-TB drug (typically an aminoglycoside) (1). Thus, there is a great need both for new antibiotics to treat M. tuberculosis and for new drug targets that avoid cross-resistance to currently used therapies.O...

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“…26 After a high dose iv injection, CPZ moved into cardiac and pulmonary circulation¯rst, damaged the respiratory chain in the mitochondria of the heart and lung, representing the disorder of respiration and ECG responded before CBF and NADH. 16 Therefore, the hypoxia to brain tissue was a mixture of circulatory and histogenous types.…”

Section: Histogenous Hypoxiamentioning

confidence: 99%

Early identification of acute hypoxia based on brain NADH fluorescence and cerebral blood flow

Shi

Sun

Mayevsky

et al. 2014

J. Innov. Opt. Health Sci.

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Hypoxia is closely related to many diseases and often leads to death. Early detection and identi¯cation of the hypoxia causes may help to promptly determine the right rescue plan and reduce the mortality. We proposed a new multiparametric monitoring method employing mitochondrial reduced nicotinamide adenine dinucleotide (NADH)°uorescence, regional re°ec-tance, regional cerebral blood°ow (CBF), electrocardiography (ECG), and respiration under six kinds of acute hypoxia in four categories to investigate a correlation between the parameter variances and the hypoxia causes. The variation patterns of the parameters were discussed, and the combination of NADH and CBF may contribute to the identi¯cation of the causes of hypoxia.

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The effect of chlorpromazine on the respiratory chain. Cytochrome oxidase

Cited by 67 publications

References 11 publications

THE EFFECT OF CHLORPROMAZINE ON ¹⁴C‐GLUCOSE METABOLISM IN MOUSE LIVER AND BRAIN

THE EFFECT OF CHLORPROMAZINE ON ¹⁴C‐GLUCOSE METABOLISM IN MOUSE LIVER AND BRAIN

Mutation of Rv2887 , a marR -Like Gene, Confers Mycobacterium tuberculosis Resistance to an Imidazopyridine-Based Agent

Early identification of acute hypoxia based on brain NADH fluorescence and cerebral blood flow

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The effect of chlorpromazine on the respiratory chain. Cytochrome oxidase

Cited by 67 publications

References 11 publications

THE EFFECT OF CHLORPROMAZINE ON 14C‐GLUCOSE METABOLISM IN MOUSE LIVER AND BRAIN

THE EFFECT OF CHLORPROMAZINE ON 14C‐GLUCOSE METABOLISM IN MOUSE LIVER AND BRAIN

Mutation of Rv2887 , a marR -Like Gene, Confers Mycobacterium tuberculosis Resistance to an Imidazopyridine-Based Agent

Early identification of acute hypoxia based on brain NADH fluorescence and cerebral blood flow

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THE EFFECT OF CHLORPROMAZINE ON ¹⁴C‐GLUCOSE METABOLISM IN MOUSE LIVER AND BRAIN

THE EFFECT OF CHLORPROMAZINE ON ¹⁴C‐GLUCOSE METABOLISM IN MOUSE LIVER AND BRAIN