Review of investigations of dichloromethane metabolism and subchronic oral toxicity as the basis for the design of chronic oral studies in rats and mice

Kirschman, John C.; Brown, Nicole M.; Coots, Robert H.; Morgareidge, Kenneth

doi:10.1016/0278-6915(86)90322-4

Cited by 17 publications

(8 citation statements)

References 6 publications

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“…This dose saturates the cytochrome P‐450 oxidative system, and yields maximal carboxyhemoglobin (COHb) values of around 10% COHb in venous or aortic blood (27–29). Previously published data have demonstrated that 500 mg/kg MC administered per os is rapidly absorbed, reaching a mean blood concentration of 60–70 mg/mL, is metabolized with a half‐life of about 3 h, and generates CO with a half‐life of 13 h and COHb with a half‐life of around 2 h (27–31). COHb levels were evaluated in heparinized venous blood using the AVOXimeter sensor (A‐VOX Systems, San Antonio, TX, USA) and expressed as the percentage of total hemoglobin.…”

Section: Methodsmentioning

confidence: 99%

Gene Transfer of Heme Oxygenase-1 and Carbon Monoxide Delivery Inhibit Chronic Rejection

Chauveau

Bouchet

Roussel

et al. 2002

American Journal of Transplantation

126

104

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The hallmark of chronic rejection is the occlusion of the artery lumen by intima hyperplasia as a consequence of leukocyte infiltration and vascular smooth muscle cell (VSMC) migration and proliferation. Heme oxygenase-1 (HO-1) is a tissue protective molecule which degrades heme into carbon monoxide (CO), free iron and biliverdin. We analyzed the effects of HO-1 gene transfer into the vessel wall using an adenoviral vector (AdHO-1) and of CO delivery in a model of chronic allogeneic aorta rejection in rats. Carbon monoxide treatment was achieved by a new pharmacological approach in transplantation using methylene chloride (MC), which releases CO after degradation. AdHO-1-mediated gene transfer into aorta endothelial cells (ECs) or CO delivery resulted in a significant reduction in intimal thickness compared to untreated or noncoding adenovirus-treated controls. Aortas transduced with AdHO-1 or treated with CO showed a reduction in the number of leukocytes as well as in the expression of adhesion molecules, costimulatory molecules and cytokines, with the gene transfer treatment displaying a more pronounced effect than the CO treatment. Conversely, CO inhibited VSMC accumulation in the intima more efficiently than AdHO-1 treatment. Gene transfer of HO-1 and pharmacological manipulation of CO are novel approaches to the analysis and treatment of chronic rejection.

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Section: Methodsmentioning

confidence: 99%

Gene Transfer of Heme Oxygenase-1 and Carbon Monoxide Delivery Inhibit Chronic Rejection

Chauveau

Bouchet

Roussel

et al. 2002

American Journal of Transplantation

126

104

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“…It is mainly catabolized by the cytochrome P-450 oxidative system and its main metabolites are CO and CO 2 [23,24]. The protective effects of MC have been associated with the production of CO [12].…”

Section: Discussmentioning

confidence: 99%

Methylene chloride protects against cecal ligation and puncture-induced acute lung injury by modulating inflammatory mediators

Pang

Dou

Pan

et al. 2010

International Immunopharmacology

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“…Most importantly, CYP2E1 activates many xenobiotics to hepatotoxic or carcinogenic products (Lieber, 1997). Also, a wide variety of CYP2E1 substrates are known to exhibit saturation kinetics (Ramsey and Young, 1978;Kirschman et al, 1986;Kreiling et al, 1986;Lof and Johanson, 1993;Dekant et al, 1995;Whysner et al, 1996;Lee et al, 2000;Vittozzi et al, 2000;Rappaport et al, 2002).…”

mentioning

confidence: 99%

Saturation Toxicokinetics of Thioacetamide: Role in Initiation of Liver Injury

Chilakapati

Shankar²,

Korrapati³

et al. 2005

Drug Metabolism and Disposition

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ABSTRACT:Thioacetamide (TA), a potent centrilobular hepatotoxicant, undergoes a two-step bioactivation mediated by microsomal CYP2E1 to TA sulfoxide (TASO), and further to TA-S,S-dioxide (TASO 2 ), a reactive metabolite that initiates cellular necrosis. Our earlier studies showed that bioactivation-mediated liver injury of TA is not doseproportional. The objective of this study was to examine whether increasing doses of TA lead to enzyme saturation, thereby resulting in lack of dose-response for injury: bioactivation of TA 3 TASO 3 TASO 2 may follow zero-order kinetics. A 12-fold dose range of TA (50, 300, and 600 mg/kg i.p.) was injected into male SpragueDawley rats. TA and TASO were quantified in plasma, liver, and urine by high-performance liquid chromatography. With increasing doses, the apparent elimination half-lives of TA and TASO increased linearly, indicating that TA bioactivation exhibits saturation kinetics. Increasing TA dose resulted in greater-than-proportional increases in plasma TA and TASO levels. The TASO/TA ratio was inversely proportional to the dose of TA. Covalent binding of 14 C-TA-derived radiolabel to liver macromolecules showed a lessthan-dose-proportionate increase with a 12-fold higher dose. Less than dose-proportional covalent binding was confirmed in liver microsomal incubations with 14 C-TA. Three-fold higher excretion of TASO was seen in urine at the highest dose (600 mg/kg) compared with the lowest dose (50 mg TA/kg). Incubation of TA with rat liver microsomes and purified baculovirus-expressed rat and human CYP2E1 Supersomes, over a concentration range of 0.01 to 10 mM, revealed saturation of TA conversion to TASO at and above 0.05 mM TA concentration, comparable to in vivo plasma and liver levels achieved upon administration of higher doses. Calculated K m values for TA (0.1 mM) and TASO (0.6 mM) suggest that the second step of TA bioactivation is 6-fold less efficient. Collectively, the findings indicate saturation of CYP2E1 at the first (TA to TASO) and second (TASO to TASO 2 ) steps of TA bioactivation.

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Review of investigations of dichloromethane metabolism and subchronic oral toxicity as the basis for the design of chronic oral studies in rats and mice

Cited by 17 publications

References 6 publications

Gene Transfer of Heme Oxygenase-1 and Carbon Monoxide Delivery Inhibit Chronic Rejection

Gene Transfer of Heme Oxygenase-1 and Carbon Monoxide Delivery Inhibit Chronic Rejection

Methylene chloride protects against cecal ligation and puncture-induced acute lung injury by modulating inflammatory mediators

Saturation Toxicokinetics of Thioacetamide: Role in Initiation of Liver Injury

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