Cell cycle and gene expression changes in response to 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in human TK6 Cells

Zhu, Huanzhang; Boobis, AR; Gooderham, Nigel J.

doi:10.1016/s0300-483x(00)90299-3

Cited by 5 publications

(8 citation statements)

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“…Increases in S-phase cells were observed in WTK1 but there was no evidence of a S-phase delay in TK6. These results are different from those of Zhu et al [21] where PhIP transformed by cells expressing human cytochrome P-450-1A2 was reported to uniquely activate the S-phase checkpoint. In our study, PhIP was activated by a rat liver homogenate (S9).…”

Section: Discussioncontrasting

confidence: 99%

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Role of p53 and mismatch repair in PhIP-induced perturbations of the cell cycle

Duc

Leong-Morgenthaler

2004

Journal of Chromatography B

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Section: Discussioncontrasting

confidence: 99%

“…Treatment of cells with CYP1A2 activated PhIP results in a S-phase delay, but does not activate either the G1 or G2-M checkpoints in the human lymphoblastoid cell line TK6 [21]. In this article, we report that PhIP activated by the metabolizing enzymes in rat liver S9 induces a G2-M cell-cycle arrest through a p53-independent mechanism.…”

Section: Introductionmentioning

confidence: 80%

Role of p53 and mismatch repair in PhIP-induced perturbations of the cell cycle

Duc

Leong-Morgenthaler

2004

Journal of Chromatography B

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“…The mechanism of PhIP induced cytotoxicity is not clear from these experiments but may be explained by the ability of PhIP to accumulate genetic damage during S-phase arrest of the cell and induce apoptosis [26,27]. Similar biochemical effects have also been observed in colonic epithelium in vivo [28].…”

Section: Discussionmentioning

confidence: 65%

Phytoalexin resveratrol attenuates the mutagenicity of the heterocyclic amines 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline

Boyce

Doehmer²,

Gooderham

2004

Journal of Chromatography B

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“…To further characterise the nature of the cytotoxicity of MIT, we examined SH-SY5Y cell cycle distribution, using flow cytometry 16,17 . SH-SY5Y cells treated with MIT appeared to be resistant to cell cycle effects except at the highest dose tested, 75 µM, where there was evidence for a G1 arrest.…”

Section: Discussionmentioning

confidence: 99%

The cellular toxicology of mitragynine, the dominant alkaloid of the narcotic-like herb, Mitragyna speciosa Korth

et al. 2015

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Toxicology ResearchDear Editor, Thank you for the reviews on our submission. The reviewers make some very good suggestions that we have incorporated into the text and the revised manuscript is now much stronger. I shall address the reviewers' comments on a point by point basis. Referee 1This is a well written paper and the experiments described, though fairly basic, are well performed and analysed. The work explores the mechanism of toxicity of mitragynine, the active alkaloid constituent of the herb Mitragyna speciosa Korth, and suggests a key molecular initiating event (MIE) that triggers the toxicity cascade.We thank the reviewer for the supportive words. The dose level at which toxicity was seen is 75µM that is some 75,000 to 750fold higher that that found in fairly high level users of the herb. This needs to be included in the abstract.We do mention this fact in the discussion along with the problems of extrapolating in vitro data to the situation in humans. To put our data in context, we also comment upon the human fatalities associated with Kratom consumption. In line with the comment and taking into consideration the reviewer's point 2, we now include new statements in the abstract and expand on this in the discussion. This is a great point. In fact references 9-11 in our manuscript give details of plasma levels of mitragynine in human fatalities associated with Kratom use. The plasma mitragynine concentrations in these individuals varied between 0.45 -1.5 microM, which is 50 fold less than the concentrations used in our studies. We have therefore included a review of these reports in our revised discussion. It Shown in both the cytoxicity assays (fig 2B) and clonogenic assays (Fig 2D) the lower doses show a marked cell proliferation. This is not commented on and some text should be included to deal with this.We have amended the text to comment on this. The reviewer makes an important point and we have reviewed the literature around this. We note that there is clear evidence in the literature of opiate mediated cell toxicity, particularly around morphine. In the revised submission we now reference reports of similar observations to ours, regarding naloxone effects on morphine toxicity and their speculation on the role of the µ receptor. Clearly the role of opioid receptors in opiate cellular toxicity remains controversial. The authors looked at the mechanism and hypothesised that the key molecular event could be interaction with the opiate receptors. This was tested using antagonists against these receptors. Naloxone that has activity particularly against the µ and ҝ receptors showed activity in reducing the toxicity but naltrindole (active against the δ receptor) did not show activity in Minor comments a. The resolution of figure 1 needs to be improved. This figure has clearly been cut and pasted from elsewhere.We have redrawn the figure using Chem-Draw. b. Figures 2A and 2B require error bars.We apologise for this oversight. The error bars have been added. Referee: 2Comments to the Author The results f...

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Cell cycle and gene expression changes in response to 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in human TK6 Cells

Cited by 5 publications

References 0 publications

Role of p53 and mismatch repair in PhIP-induced perturbations of the cell cycle

Role of p53 and mismatch repair in PhIP-induced perturbations of the cell cycle

Phytoalexin resveratrol attenuates the mutagenicity of the heterocyclic amines 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline

The cellular toxicology of mitragynine, the dominant alkaloid of the narcotic-like herb, Mitragyna speciosa Korth

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