Inactivation of rat liver cytochrome P450 (P450) by N,N-dimethylformamide and N,N-dimethylacetamide

Tolando, Roberto; Zanovello, Alberta; Ferrara, Roberta; Iley, Jim; Manno, Maurizio

doi:10.1016/s0378-4274(01)00384-8

Cited by 34 publications

(11 citation statements)

References 51 publications

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“…[30] Accumulation of DMF would inhibit its biodegradation. [9] Cocultured with DDC, it partially lowered the rate of metabolism and thus changed the dominant species of secondary metabolites after 24 h exposure.…”

Section: Discussionmentioning

confidence: 99%

“…[5][6][7] Until now, it is believed that the hepatotoxicity of DMF is due to the formation of toxic intermediates, which is metabolized by cytochrome P4502E1 (CYP2E1). [8] Oxidation of DMF generated N-(hydroxymethyl)-N-methylformamide (HMMF) and the other derivatives, [9] which resulted in H 2 O 2 accumulation in hepatocytes [10] . Recently, one epidemiological investigation has revealed that the body burden of DMF metabolites was highly associated with DMF-induced liver disease.…”

Section: Introductionmentioning

confidence: 99%

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Study on the potential way of hepatic cytotoxicity of N,N‐dimethylformamide

Wang

2018

J Biochem & Molecular Tox

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The intermediate metabolites and redox status imbalance were supported as the two major points for N,N-dimethylformamide (DMF)-induced hepatotoxicity. However, the potential mechanism has not yet been concerned. By applying two inhibitors, this study tried to seek the major role in DMF-induced toxicity on HL7702 cell. We observed that DMF induced cell apoptosis through mitochondrial-dependent and p53 pathway. Inhibition reactive oxygen species by catalase remarkably attenuated the mitochondrial transmembrane potential (MMP), apoptotic proteins, and apoptosis. On the contrary, it reduced the biodegradation rate of DMF by coincubation with CYP2E1 antagonist (DDC) partially reduced late apoptosis. However, the change in MMP, the ratio of Bax to Bcl-xl, and cleaved-caspase 9 was not attenuated by DDC. The pathway in DDC coincubation groups was related to the p53 rather than the mitochondrial pathway. Restoring the redox balance during biodegradation is much more effective than attenuating the metabolite rate of DMF. This study may provide a suitable prevention method to occupational workers.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Study on the potential way of hepatic cytotoxicity of N,N‐dimethylformamide

Wang

2018

J Biochem & Molecular Tox

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“…Carbon tetrachloride (Manno et al, 1988) and halothane (Manno et al, 1991) were shown to inactivate human liver microsomal P450s by irreversibly modifying the heme cofactor. A similar inactivation process was observed with N,N-dimethylformamide and N,N-dimethylacetamide (Tolando et al, 2001). Small percentages of commonly used water soluble organic solvents such as acetonitrile and methanol produce a significant inhibition of the activity of human P450s (Busby et al, 1999;Easterbrook et al, 2001;Hickman et al, 1998).…”

Section: Introductionmentioning

confidence: 64%

Activity of human P450 2D6 in biphasic solvent systems

Zhao

Tan

Ferras

et al. 2007

Biotech & Bioengineering

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Several limitations have restricted the use of P450 enzymes in synthesis, including the narrow substrate specificity of some P450 isoforms, the need for a redox partner and an expensive cofactor, incompatibility with organic solvents, and poor stability. We previously demonstrated that the natural redox partner and cofactor of the promiscuous P450s 3A4 and 2D6 can be efficiently substituted with some cheap hydrogen peroxide donors or organic peroxides. We report here that P450 2D6 maintains as much as 76% of its activity when used in buffer/organic emulsions. Product formation in biphasic solvent systems is comparable whether the natural redox partner and cofactor are used, or a surrogate. As reported for other enzymes, a correlation is observed between the logP and the suitability of a solvent for enzymatic activity. Moreover, the utility of our system was established by demonstrating the transformation of a novel hydrophobic substrate, not modified by P450 2D6 in the absence of organic solvent.

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“…In humans, the metabolism of DMA produces acetamide and Nmethylacetamide, as identified in the urine of workers exposed to the compound (71). It was proposed that the attack on heme by free radical metabolites is responsible for the hepatotoxicity of DMA (72).…”

Section: Nn-dimethylacetamide (Dma) and Busulfanmentioning

confidence: 99%

In vitro elucidation of the metabolic fate of the anticancer drug busulfan

Younis¹

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Busulfan is a bifunctional alkylating agent that is used to treat mylogenous leukemia. The major elimination pathway of busulfan is through glutathione-Stransferase (GST) catalyzed conjugation to form glutathione sulfonium conjugate. The aim of this work is to elucidate the novel metabolic pathways of busulfan that may explain its toxicity. The observed data showed that busulfan is not a substrate for CYP450. The sulfonium ion conjugate of busulfan was found to be inactive as it did not inhibit GST in human liver cytosol, did not react with 4-(4-nitrobenzyl)pyridine, did not induce apoptosis in NCI-H460 cells, and was not stable in basic conditions with a half life of 6.0 hours at pH 7.4. The degradation products were identified to be tetrahydrothiophene and dehydroglutathione. Dehydroglutathione is a glutathione analogue in which the cysteine moiety is replaced by dehydroalanine moiety, which makes it a Michael acceptor. This secondary metabolite of busulfan produced cytotoxicity against C6 glioma cells and reacted in vitro with sulfhydryl nucleophiles such as glutathione and cysteine. An alternative metabolic pathway for the sulfonium ion conjugate of busulfan is through the mercapurate pathway which will lead to the formation of the cysteine sulfonium conjugate of busulfan (THT-A). THT-A was found to undergo a non-enzymatic β-elimination reaction at pH 7.4 and 37 ºC to yield tetrahydrothiophene, pyruvate and ammonia. This reaction is accelerated by a) rat liver, kidney and brain homogenates, b) isolated rat liver mitochondria, and c) pyridoxal 5'phosphate (PLP). A PLP-dependent enzyme in rat liver cytosol that catalyzes a β-lyase reaction with THT-A was identified as cystathionine γ-lyase. This unusual drug metabolism pathway represents an alternate route for intermediates in the mercapturate pathway. Islam Rasem Younis IN VITRO ELUCIDATION OF THE METABOLIC FATE OF THE ANTICANCER DRUG BUSULFAN iii DEDICATION To the soul of my Dad Dr. Rasem M. Younis "may he rest in peace" and my beloved Mom Fatima A. Faraj iv ACKNOWLEDMENTS The process of conducting research is obviously not possible without the personal and practical support of numerous people. Thus, I owe my gratitude to all those people who have made this dissertation possible and because of whom my graduate experience has been one that I will cherish forever. I am deeply indebted to my esteemed advisor Dr. Patrick Callery, whose help, stimulating discussions, suggestions, understanding, encouragement, and patience helped me all the time to finish up the work. I am eternally grateful to my co-advisor Dr. William Petros for his assistance, guidance, and giving me the opportunity to perform pharmacokinetics studies. I was lucky to have the opportunity to work with both distinguished investigators. Their mentorship was paramount in providing a well rounded experience consistent with my long-term career goals. They encouraged me to not only grow as an experimentalist but also as an instructor and an independent thinker. I am not sure how many graduate students ...

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Inactivation of rat liver cytochrome P450 (P450) by N,N-dimethylformamide and N,N-dimethylacetamide

Cited by 34 publications

References 51 publications

Study on the potential way of hepatic cytotoxicity of N,N‐dimethylformamide

Study on the potential way of hepatic cytotoxicity of N,N‐dimethylformamide

Activity of human P450 2D6 in biphasic solvent systems

In vitro elucidation of the metabolic fate of the anticancer drug busulfan

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