Paracetamol‐Induced Spindle Disturbances in V79 Cells with and without Expression of Human CYP1A2

Jensen, Klaus Gjervig; Poulsen, Henrik E.; Doehmer, Johannes; Loft, Steffen

doi:10.1111/j.1600-0773.1996.tb00209.x

Cited by 9 publications

(7 citation statements)

References 37 publications

(31 reference statements)

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“…The subsequent more detailed screen that was focused on nuclear processes, and included mutants of essential genes and multiple concentrations of APAP, did not corroborate DNA repair as a pathway involved in APAP toxicity, consistent with the general safety profile of the drug. However, APAP is reported to effect mitosis and disturb spindles in mammalian cells [14]. Perhaps Mms2 and Ubc13 have another role besides modification of PCNA related to APAP tolerance or ubiquitin homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“…For example, Miyakawa et al (2015) showed cytochrome P450 independent toxicity in mouse hepatocytes, especially at higher APAP concentrations [13], while Jensen et al (1996) reported toxicity with and without expression of cytochrome P450, which in both cases caused induction of spindle disturbances in Chinese hamster V79 cells [14]. Srikanth et al (2005) observed APAP toxicity in yeast in the absence of NAPQI-derived metabolites, while overexpression of ABC-transporters Snq2 and Flr1 resulted in increased drug resistance [15].…”

Section: Introductionmentioning

confidence: 99%

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The effect of acetaminophen on ubiquitin homeostasis in Saccharomyces cerevisiae

Huseinovic¹,

Leeuwen

Welsem

et al. 2017

PLoS ONE

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Acetaminophen (APAP), although considered a safe drug, is one of the major causes of acute liver failure by overdose, and therapeutic chronic use can cause serious health problems. Although the reactive APAP metabolite N-acetyl-p-benzoquinoneimine (NAPQI) is clearly linked to liver toxicity, toxicity of APAP is also found without drug metabolism of APAP to NAPQI. To get more insight into mechanisms of APAP toxicity, a genome-wide screen in Saccharomyces cerevisiae for APAP-resistant deletion strains was performed. In this screen we identified genes related to the DNA damage response. Next, we investigated the link between genotype and APAP-induced toxicity or resistance by performing a more detailed screen with a library containing mutants of 1522 genes related to nuclear processes, like DNA repair and chromatin remodelling. We identified 233 strains that had an altered growth rate relative to wild type, of which 107 showed increased resistance to APAP and 126 showed increased sensitivity. Gene Ontology analysis identified ubiquitin homeostasis, regulation of transcription of RNA polymerase II genes, and the mitochondria-to-nucleus signalling pathway to be associated with APAP resistance, while histone exchange and modification, and vesicular transport were connected to APAP sensitivity. Indeed, we observed a link between ubiquitin levels and APAP resistance, whereby ubiquitin deficiency conferred resistance to APAP toxicity while ubiquitin overexpression resulted in sensitivity. The toxicity profile of various chemicals, APAP, and its positional isomer AMAP on a series of deletion strains with ubiquitin deficiency showed a unique resistance pattern for APAP. Furthermore, exposure to APAP increased the level of free ubiquitin and influenced the ubiquitination of proteins. Together, these results uncover a role for ubiquitin homeostasis in APAP-induced toxicity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The effect of acetaminophen on ubiquitin homeostasis in Saccharomyces cerevisiae

Huseinovic¹,

Leeuwen

Welsem

et al. 2017

PLoS ONE

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“…In each experiment, cultures were divided into seven treatment groups: (1) negative control (medium alone); (2) positive control (3 nM estradiol); (3) 3 nM estradiol + 0.1 mM acetaminophen; (4-7) 0.03 mM, 0.1 mM, 0.3 mM, and 1 mM acetaminophen, respectively. The acetaminophen concentrations ranged from therapeutic (0.03-0.1 mM) to toxic (1 mM) plasma level counterparts in humans (Forrest et al, 1982;Jensen et al, 1996). The estradiol concentration corresponds to physiological plasma levels in women (Vohrerr, 1967).…”

Section: Methodsmentioning

confidence: 99%

Acetaminophen Alters Estrogenic Responsesin Vitro:Stimulation of DNA Synthesis in Estrogen-Responsive Human Breast Cancer Cells

Harnagea-Theophilus

Miller

1998

Toxicological Sciences

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“…The acetaminophen concentrations reflect therapeutic (0.03-0.1 mM) and toxic (1 mM) plasma level counterparts in humans (Forrest et al, 1982;Jensen et al, 1996). The estradiol concentration corresponds to physiological plasma levels in pregnant women (Vohrerr, 1967;Berne and Levy, 1993).…”

Section: Cell Culturementioning

confidence: 99%

“…The typical therapeutic adult dose of acetaminophen is 0.325-1.3 g administered every 4-6 hours (Kastrup, 1981), resulting in plasma concentrations of approximately 0.03-0.12 mM (Forrest et al, 1982). Doses over 10 g are toxic (Kastrup, 1981) and lead to plasma concentrations of approximately 1 mM (Jensen et al, 1996). type and mutant ER's.…”

Section: Data Summarymentioning

confidence: 99%

Acetaminophen stimulates proliferation of breast cancer cells

Theophilus¹

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Acetaminophen is a common analgesic/antipyretic. This research projected investigated the interaction of acetaminophen with breast cancer cells. The first goal was to determine if acetaminophen induces proliferation in cancerous and normal, human breast cells. Pharmacological concentrations of acetaminophen stimulated proliferation (3 H-thymidine incorporation into DNA, % S phase cells, cell numbers) of estrogen and progesterone receptor positive (ER+/PR+) but not of ER-/PR+ or of ER-/PR-cancer or normal breast cells. The second goal was to determine if estrogen receptors play a role in acetaminophen-induced proliferation of ER+ breast cancer cells. Antiestrogens inhibited acetaminophen-induced proliferation, suggesting that ERs are involved in proliferation. However, acetaminophen did not bind to ERs in ER+ breast cancer cells, indicating that while acetaminophen mimics some of estradiol effects, it does so by a different mechanism. The third goal was to determine if the p-phenol moiety in acetaminophen plays a role in the proliferation of ER+ breast cancer cells. The effects of the positional isomers of acetaminophen on proliferation followed the order: p-> m-> oacetamidophenol. These findings indicate that the p-phenol is important for proliferation of ER+ breast cancer cells. The fourth goal was to determine if metabolism of acetaminophen occurs in breast cancer cells. Microsomes from ER+ breast cancer cells that undergo proliferation in response to acetaminophen did not metabolize acetaminophen to detectable levels except when cells were pretreated with inducers of cytochrome P450. By contrast, ER-breast cancer cells metabolized acetaminophen to detectable levels in both, cells non-induced and induced with cytochrome P450 inducers. The fifth goal was to determine if acetaminophen affects tumor growth in nude mice inoculated with ER+ human breast cancer cells. Acetaminophen (150 mg/kg/day), like estradiol, stimulated tumor growth relative to negative controls up to day 36 following inoculation with ER+ cells. However, after day 36, all tumors regressed. Taken together, the data in this project are novel and help to understand the interaction of acetaminophen with breast cancer cells, an area largely understudied. iii Dedication To Paul, who enriches my life Special thanks to Dr. Miller whose energy and enthusiasm inspired me and whose great advice I will always remember. Thanks to Dr. Reasor for his incredible care and valuable advice. Thanks to Drs. Strobl, Craig and Castranova for helping me with the committee work. Thanks to Dr. Stamm whose competent input was always appreciated and intellectually stimulating. Thanks to Doina Jickich who advised me to apply for this graduate program. Thanks to my husband for all his help and support. v

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Paracetamol‐Induced Spindle Disturbances in V79 Cells with and without Expression of Human CYP1A2

Cited by 9 publications

References 37 publications

The effect of acetaminophen on ubiquitin homeostasis in Saccharomyces cerevisiae

The effect of acetaminophen on ubiquitin homeostasis in Saccharomyces cerevisiae

Acetaminophen Alters Estrogenic Responsesin Vitro:Stimulation of DNA Synthesis in Estrogen-Responsive Human Breast Cancer Cells

Acetaminophen stimulates proliferation of breast cancer cells

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