Mutagenicity studies with X-ray-contrast media, analgesics, antipyretics, antirheumatics and some other pharmaceutical drugs in bacterial, Drosophila and mammalian test systems

King, M.-T.; Beikirch, H.; Eckhardt, K.; Gocke, Elmar; Wild, D.

doi:10.1016/0165-1218(79)90005-3

Cited by 83 publications

(16 citation statements)

References 17 publications

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“…In mice dosed with paracetamol in vivo chromosome aberrations in bone marrow cells were demonstrated from a single dose of 200 mg/kg body weight and sister chromatid exchange from 50 mg/kg (Giri et al 1992), whereas 450 mg/ kg failed to induce micronuclei (King et al 1979). In agreement, prior glutathione depletion and 3-600 mg paracetamol per kg body weight were required to demonstrate covalent binding of NAPQI to DNA and strand breaks in mouse liver (Honglo et al 1994).…”

Section: Discussionmentioning

confidence: 92%

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

Jensen

Poulsen

Doehmer³

et al. 1996

Pharmacology & Toxicology

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Spindle disturbing effects in terms of c-mitosis and cytotoxicity of paracetamol were investigated in two Chinese hamster V79 cell lines, one of which (V79MZh1A2) was transfected with human CYP1A2. This enzyme catalyses the oxidative formation of the reactive paracetamol metabolite, NAPQI, believed to initiate hepatoxicity by covalent binding to proteins after overdose. In the native V79 cell line paracetamol increased c-mitosis frequency in a concentration dependent manner from 8.7 + or - 3.5% (control) to 66 + or - 18% at 20 mM. A significant increase to 13.3 + or - 3.5% was first seen at 2.5 mM in the native cell line (P<0.05). In the V79MZh1A2 cells the concentration-effect curve was slightly shifted to the left (P<0.05) with c-mitosis frequency increased to 12.1 + or - 2.6% (P<0.05) at 1 mM paracetamol. At 5 mM paracetamol the c-mitosis frequency was 14.4 + or - 5.0% and 19.0 + or - 3.8% in the native and CYP1A2 expressing cell lines, respectively (P<0.05). At 20 mM paracetamol the c-mitosis frequency was 61 + or - 10% in the V79MZh1A2 cells. Cell survival was reduced to approximately 50% at 5-10 mM paracetamol in both cell lines. At 20 mM paracetamol survival was further decreased to 39 + or - 9% in V79MZh1A2 cells only (P<0.05). The present study demonstrated that paracetamol may disturb the spindle of dividing cells conveying a risk of aneuploidy. The spindle disturbing effect was only slightly enhanced by expression of CYP1A2, suggesting that metabolic activation plays only a minor role in this genotoxic effect. The reduction of survival mirrored the increase in c-mitosis frequency.

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Section: Discussionmentioning

confidence: 92%

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

Jensen

Poulsen

Doehmer³

et al. 1996

Pharmacology & Toxicology

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“…The SCF concluded that the large number of mutagenicity tests in vitro and in vivo confirmed the absence of genotoxic activity of quinine; however, the reports on which this conclusion was based could not be retrieved by the Panel. Quinine dihydrochloride, along with a number of other chemicals, was tested in bacterial reverse mutation tests with Salmonella typhimurium (S. typhimurium) strains TA98, TA100, TA1535, TA1537 and TA1538 using the plate-incorporation methodology and Escherichia coli (strain K12/343/113), both in the absence and presence of metabolic activation (King et al, 1979). The material tested was purchased from EGA-Chemie GmbH and Co. KG, Steinheim/Albuch, Germany, exhibiting the correct melting point and elemental analysis and was used without further purification.…”

Section: Genotoxicity Studiesmentioning

confidence: 99%

“…The in vivo studies on quinine dihydrochloride and quinine hydrochloride were performed by King et al (1979) and Münzner and Renner (1983) and published along with data on in vitro assays described above.…”

Section: In Vivomentioning

confidence: 99%

Scientific Opinion on Flavouring Group Evaluation 35, Revision 1 (FGE.35Rev1): Three quinine salts from the Priority list from chemical group 30

Flavourings¹

2015

EFS2

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The Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids of the European Food Safety Authority was requested to evaluate three flavouring substances in the Flavouring Group Evaluation 35, Revision 1, using the Procedure in Commission Regulation (EC) No 1565/2000. The present revision includes new specification data on quinine sulphate [FL‐no: 14.152] and quinine monohydrochloride dihydrate [FL‐no: 14.155], new intake data on all three candidate substances and toxicological and genotoxicity data on quinine hydrochloride [FL‐no: 14.011] and quinine monohydrochloride dihydrate [FL‐no: 14.155], as well as two structurally related quinine salts (quinine dihydrochloride and deoxyquinine). A search in open literature has been made and the relevant data are presented. This evaluation concerns only the use of these quinine salts in beverages, where they are legally permitted. Because of the availability of well conducted human studies at much higher quinine exposures than those occurring when quinine is used as flavouring substance and which were considered in this FGE.35Rev1, the Panel considered the use of the Procedure for these substances inappropriate. However, based on human data available on quinine, the Panel concluded that the quinine salts are not expected to be of safety concern at their estimated level of intake as flavouring substances, provided that hypersensitivity reactions are avoided by the legally required labelling of quinine‐containing beverages. The Panel noted that a very high intake (e.g. more than 1 litre) of non‐alcoholic beverages containing quinine or its salts at the maximum permitted level could result in adverse health effects in humans. Besides the safety assessment of these three flavouring substances, the specifications for the materials of commerce have also been considered. Adequate specifications, including complete purity criteria and identity, have been provided for all three candidate substances.

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“…The mutagenicity of the pyrazolone analgesic aminopyrine (AM) (1) is only irrelevant if examined out of context. It is true that, in the majority of reported cases of urinary tract tumors presumably associated with analgesic abuse, which have originated from Sweden, the most frequently identified formulations have contained the pyrazolone analgesic antipyrine (AT), phenacetin (P), and caffeine (C).…”

mentioning

confidence: 99%

“…It is true that, in the majority of reported cases of urinary tract tumors presumably associated with analgesic abuse, which have originated from Sweden, the most frequently identified formulations have contained the pyrazolone analgesic antipyrine (AT), phenacetin (P), and caffeine (C). However, the availability of AM has been widespread throughout Europe (1,2) and was a component of at least some of the formulations identified in case reports of neoplasia attributed to P in presumed situations of analgesic abuse.…”

mentioning

confidence: 99%

Phenacetin Safety

MACKLIN¹,

WELCH²

1980

Science

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Mutagenicity studies with X-ray-contrast media, analgesics, antipyretics, antirheumatics and some other pharmaceutical drugs in bacterial, Drosophila and mammalian test systems

Cited by 83 publications

References 17 publications

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

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

Scientific Opinion on Flavouring Group Evaluation 35, Revision 1 (FGE.35Rev1): Three quinine salts from the Priority list from chemical group 30

Phenacetin Safety

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