Comparative Cytotoxicity of Monocrotaline and Its Metabolites in Cultured Pulmonary Artery Endothelial Cells

Taylor, D. W.; Wilson, Dennis W; Lamé, Michael W.; Dunston, S. D.; Jones, A. Daniel; Segall, H. J.

doi:10.1006/taap.1996.8083

Cited by 26 publications

(12 citation statements)

References 34 publications

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“…Because components represent sources of variation, it can be concluded that the absorption of tissues in the NIR regions is complex and due to many components. It is known that MCT metabolites and other hypertensive conditions produce chemical changes in the compositions of tissue (e.g., proteins, carbohydrates, lipids, DNA) [8,[22][23][24][25]. Such changes were detected by the NIR technique and classified as components by the PLS method.…”

Section: Discussionmentioning

confidence: 99%

Pulmonary hypertension

McLaughlin

Rich²

2004

Current Problems in Cardiology

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a b s t r a c tA new method has been developed for the determination of tissue pathology caused by chronic hypoxia and monocrotaline toxicity. The method is based on the use of near-infrared (NIR) spectrophotometry to measure spectra of lung tissue from normal chronic hypoxia (CH) and monocrotaline (MCT) models of pulmonary hypertension (PH), followed by analysis using multivariate methods, that is, principal component analysis (PCA) and partial least squares (PLS). Synergistic use of NIR with the PCA/PLS method makes it possible, for the first time, not only to divide different lung tissue samples into their respective groups (normal, CH, and MCT) but also to gain insight into mechanisms of PH caused by CH and MCT toxicity. Specifically, MCT metabolites and other hypertensive conditions are known to produce subtle and minor chemical changes in the compositions of tissue (e.g., proteins, carbohydrates, lipids). Although these changes were detected by the NIR technique, they were too small to be discerned through visual inspection of the spectra. However, they can be accurately classified and properly assigned by the PCA/PLS method. The fact that different tissue types can be accurately divided into their corresponding groups by the NIR and PCA/PLS methods suggests that chemical alterations and mechanisms of pulmonary vascular remodeling and PH induced by MCT are different from those induced by CH.Ó 2009 Elsevier Inc. All rights reserved.Monocrotaline (MCT) 2 is an 11-membered macrocyclic diester member of the pyrrolizidine alkaloid family of plant toxins that produces a delayed onset yet progressive pulmonary vascular disease resulting in pulmonary hypertension (PH) in Sprague-Dawley rats [1][2][3]. Therefore, MCT-induced PH has been used as a model for the study of chronic pulmonary vascular diseases in humans since 1961 [4]. Nevertheless, the exact mechanism by which MCT causes pulmonary toxicity is still not completely understood [3]. Considerable efforts have been made by many research groups to elucidate the mechanism [5][6][7][8]. Some studies have shown monocrotaline pyrroles to react with DNA and other cell macromolecules [9][10][11][12]. Unfortunately, to date, only limited success has been made. This is probably due to the lack of a technique that can noninvasively detect and identify MCT and all of its intermediates and products during its biochemical transformation processes. Near-infrared (NIR) multispectral imaging technique may be the solution to this problem. We have succeeded in developing a novel NIR multispectral imaging (NIR-MSI) instrument that can provide, for the first time, the means to noninvasively, sensitively (single pixel resolution), and rapidly (ms) record not at a single wavelength as in NIR bioimaging instruments but rather on an entire NIR absorption spectrum (as with a Fourier transform [FT]-IR spectrophotometer) and not just one spectrum but rather tens of thousands of spectra at tens of thousands of different locations within a sample during a period as short as a few millise...

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Section: Discussionmentioning

confidence: 99%

Pulmonary hypertension

McLaughlin

Rich²

2004

Current Problems in Cardiology

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“…The circulatory proximity of the liver to the lung endothelium, the increased thymidine uptake, the decreased 5-HT clearance, and the extravasculature leakage of large macromolecules in the pulmonary capillaries demonstrate that monocrotaline intoxication targets the pulmonary endothelium (269,273). In vitro experiments have demonstrated that monocrotaline pyrrole can impair endothelial barrier function (274), inhibit cell proliferation (275), prolong cell cycle arrest in the G2-M phase (276), and promote apoptosis (277). Apoptosis occurs in rat pulmonary artery endothelial cells (PAEC) following the in vivo administration of monocrotaline (278).…”

Section: Ros and Vascular Remodeling In Animal Models Of Pulmonarymentioning

confidence: 99%

Reactive Oxygen Species in Pulmonary Vascular Remodeling

Aggarwal

Groß

Sharma

et al. 2013

Comprehensive Physiology

126

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The pathogenesis of pulmonary hypertension is a complex multifactorial process that involves the remodeling of pulmonary arteries. This remodeling process encompasses concentric medial thickening of small arterioles, neomuscularization of previously nonmuscular capillary-like vessels, and structural wall changes in larger pulmonary arteries. The pulmonary arterial muscularization is characterized by vascular smooth muscle cell (SMC) hyperplasia and hypertrophy. In addition, in uncontrolled pulmonary hypertension, the clonal expansion of apoptosis-resistant endothelial cells leads to the formation of plexiform lesions. Based upon a large number of studies in animal models, the three major stimuli that drive the vascular remodeling process are inflammation, shear stress and hypoxia. Although, the precise mechanisms by which these stimuli impair pulmonary vascular function and structure are unknown, reactive oxygen species (ROS)-mediated oxidative damage appears to play an important role. ROS are highly reactive due to their unpaired valence shell electron. Oxidative damage occurs when the production of ROS exceeds the quenching capacity of the anti-oxidant mechanisms of the cell. ROS can be produced from complexes in the cell membrane (nicotinamide adenine dinucleotide phosphate-oxidase), cellular organelles (peroxisomes and mitochondria), and in the cytoplasm (xanthine oxidase). Furthermore, low levels of tetrahydrobiopterin (BH4) and L-arginine the rate limiting co-factor and substrate for endothelial nitric oxide synthase (eNOS), can cause the uncoupling of eNOS, resulting in decreased NO production and increased ROS production. This review will focus on the ROS generation systems, scavenger antioxidants, and oxidative stress associated alterations in vascular remodeling in pulmonary hypertension.

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“…Furthermore, when the metabolic activation was completely inhibited by ketoconazole, the amount of deacetylclivorine formed in a 1-h incubation significantly increased from 19.44 ؎ 3.00 to 54.87 ؎ 9.30 nmol/mg protein, suggesting that the two pathways compete with each other. Therefore, the lower susceptibility of female SD rats to clivorine intoxication is suggested to be caused by the significantly higher extent of the direct hydrolysis and a lower degree of the metabolic activation.Pyrrolizidine alkaloid (PA) poisoning has drawn worldwide attention because of a wide distribution of PA-containing plants and their induced serious and diversified toxicities, especially hepatotoxicity and carcinogenicity (Mattocks, 1968;Mori et al, 1985;Huxtable, 1989;Buhler et al, 1990;Fu et al, 2002Fu et al, , 2004, as well as pneumotoxicity (Huxtable, 1990;Taylor et al, 1997), neurotoxicity (Roeder, 2000), and embryotoxicity (Tu et al, 1988). Two types of PA, namely, retronecine and otonecine, are mainly responsible for the PA-induced hepatotoxicity (Mori et al, 1985;Huxtable, 1989;Buhler et al, 1990;Fu et al, 2004).…”

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confidence: 99%

Deacetylclivorine: A Gender-Selective Metabolite of Clivorine Formed in Female Sprague-Dawley Rat Liver Microsomes

Lin

Tang²,

Liu³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Clivorine, a naturally occurring pyrrolizidine alkaloid, causes liver toxicity via its metabolic activation to generate toxic metabolite (pyrrolic ester). Female Sprague-Dawley (SD) rats are reported to be less susceptible to clivorine intoxication than male SD rats. However, the biochemical mechanism causing such gender difference is largely unknown. The present study investigated hepatic microsomal metabolism of clivorine in female rats to delineate the mechanism of the gender difference. Two pathways, which directly metabolize clivorine, were observed. First, the metabolic activation to produce the toxic pyrrolic ester followed by formations of bound pyrroles, dehydroretronecine, 7-glutathionyldehydroretronecine, and clivoric acid were found in female rats, and CYP3A1/2 isozymes were identified to catalyze the metabolic activation. Compared with male rats (ϳ21%), the metabolic activation in female rats was significantly lower (ϳ4%) possibly because of significantly lower CYP3A1/2 levels expressed in female rats. Second, a direct hydrolysis to generate the novel female rat-specific metabolite deacetylclivorine was shown as the predominant pathway (ϳ16% clivorine metabolism) in female rat liver microsomes and was determined to be mediated by microsomal hydrolase A. Furthermore, when the metabolic activation was completely inhibited by ketoconazole, the amount of deacetylclivorine formed in a 1-h incubation significantly increased from 19.44 ؎ 3.00 to 54.87 ؎ 9.30 nmol/mg protein, suggesting that the two pathways compete with each other. Therefore, the lower susceptibility of female SD rats to clivorine intoxication is suggested to be caused by the significantly higher extent of the direct hydrolysis and a lower degree of the metabolic activation.Pyrrolizidine alkaloid (PA) poisoning has drawn worldwide attention because of a wide distribution of PA-containing plants and their induced serious and diversified toxicities, especially hepatotoxicity and carcinogenicity (Mattocks, 1968;Mori et al., 1985;Huxtable, 1989;Buhler et al., 1990;Fu et al., 2002Fu et al., , 2004, as well as pneumotoxicity (Huxtable, 1990;Taylor et al., 1997), neurotoxicity (Roeder, 2000), and embryotoxicity (Tu et al., 1988). Two types of PA, namely, retronecine and otonecine, are mainly responsible for the PA-induced hepatotoxicity (Mori et al., 1985;Huxtable, 1989;Buhler et al., 1990;Fu et al., 2004). Clivorine, a representative toxic otonecine-type PA, is present in many Ligularia species and especially exists as a predominant PA in the traditional Chinese medicinal herb Ligularia hodgsonii Hook (Lin et al., 2000b;Xia et al., 2004). Clivorine has been reported to cause hepatotoxicity and carcinogenicity in rodents and a positive mutagenic response in the Ames test in the presence of rat liver homogenates, suggesting the importance of hepatic metabolic activation in its intoxication (Yamanaka et al., 1979;Kuhara et al., 1980;Xia et al., 2004). In our previous studies, hepatic microsomal metabolism of clivorine in male Sprague-Dawle...

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Comparative Cytotoxicity of Monocrotaline and Its Metabolites in Cultured Pulmonary Artery Endothelial Cells

Cited by 26 publications

References 34 publications

Pulmonary hypertension

Pulmonary hypertension

Reactive Oxygen Species in Pulmonary Vascular Remodeling

Deacetylclivorine: A Gender-Selective Metabolite of Clivorine Formed in Female Sprague-Dawley Rat Liver Microsomes

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