https://www.koreabiomed.com/news/articleView.html?idxno=21377
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Any knowledge of the limit that manufactures have been working against?
Prof @ymleefn any insights?
EMA CMDh requested to NcWP for N-nitroso tamsulosin AI limit derivation in its April 2023 meeting. So its AI is in progress work…
In Australia, the TGA has set a limit of 18ng per day
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Health Canada published a limit of 18ng per day.
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Additionally ANVISA also include Nitroso tamsulosine in its recently updated (Version 3) guidance on Control of Nitrosoamine impurities with same AI i.e 18 ng/day as like health Canada and TGA
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There are some errata in this paper. For example:
- Citation 18 (Li 2023) contains Ames test positive data on N-nitroso-propanolol, whereas you say this paper shows Ames test negativity on N-nitroso-propanolol:
- The statement that nitrosamines exist that can only be activated by irradiation is supported by NMOR as an example. However, for NMOR literature exists supporting enzyme activation, literature on NMOR mutagenicity/carcinogenicity studies can counter the relevance of this citation to support the statement:
I’m also missing reference to recent literature studying the correlation between nitrosamine carcinogenicity and Ames test data:
At the same time, it is difficult to understand the critique on the Ames test for nitrosamines, now that the embraced hypothesis of photocarcinogenicity is also often investigated with such or similar in vitro test systems using irradiation to activate the nitrosamine (this includes citation 31 on NMOR though non-cited literature exist to support the NMOR accumulates in skin)?
I’m also wondering why nitrosoproline literature is not considered?
Though the mechanism described for irradiation activated metabolization of nitrosoproline is different to the described irradiation-mediated alpha-hydroxylation of NMOR with a link with phosphate, it seems this case is well-described in peer reviewed literature.
Considering that proline can endogenously nitrosate to nitrosoproline (cf. also the use of nitrosoproline as an urinary biomarker) and that proline is obviously quite abundant (but nitrosoproline not per se accumulating in skin maybe), how likely is the contribution of NDSRIs really in absence of proof exposure exists and that they are accumulating in skin (or at least more than nitrosoproline) and can be photoactivated (at leas as good as activated structures, cf. for example COOH mechanistic role in proline)? Shouldn’t in absence of such data bigger populations be studied, studying the prevalence of skin cancer in groups taking and not taking the medicine, with a reflection on geography ?
- doi.org/10.1016/j.mrgentox.2017.06.0037
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- Mutation, DNA strand cleavage and nitric oxide formation caused by N -nitrosoproline with sunlight: a possible mechanism of UVA carcinogenicity | Carcinogenesis | Oxford Academic
Any particular reason to not consider the photosensitivity of tamsulosin itself?
I can repeat:
- Citation 18 (Li 2023) contains Ames test positive data on N-nitroso-propanolol, whereas you say this paper shows Ames test negativity on N-nitroso-propanolol:
Please read the supplementary information of Li 2023.
You are referring to “completely new way”, yet citing only NMOR photo-induced genotoxicity (which has been indicated to be linked with alpha-hydroxylation and phosphate so far (contrary to nitrosoproline where the COOH plays a mechanistic role) - thus showing a mechanistic parallel and is not new science) and referring to DNA alkylation checks (linked to NDMA exposure) which can’t distinct with enzyme-based mechanisms and are in fact indicative of metabolic activation? Of note, NDSRIs are not per se theoretically methylating agents, this depends on the N-substitution patterns and the likelihood of chain-shortening mechanisms, but can be checked by building in a radiolabeled carbon as part of the alpha-CH2 (if present) and checking for radiolabeled methylated guanine (this again not having an automatic link with proving photo-activation in the standard design of experiments).
Every paper I have seen on NMOR photo-induced genotoxicity that discusses mechanistic explanations on what happens with NMOR after photo-induction to explain mutagenicity, discusses alpha-hydroxylated NMOR as a metabolite (as proven experimentally) and the dependency on phosphate or similar ions (as proven experimentally) (conjugation link?). What paper presents something else that goes further than suggesting radical-based chemistry?
In proline there is anchimeric assistance of the COOH hence the significant difference in metabolisation mechanism upon photo-activation. Noteworthy, this literature is also much more developed.
Mechanistic understanding on what happens with a nitrosamine when you irradiate it, seems important to me to evaluate if this differentiates the risk or not, to be able to ask the question: could one of the enzymes typically present in liver homogenate (based on proteomics characterisation data) activate a pathway to the same type of metabolite?
I assume you read this paper you cite in your published work? I can’t provide copies of papers subject to copy rights, hopefully you can finally get a copy, as it is such an important reflection of the NMOR state of the art for you.
I have already tried to suggest a few times that this new 2024 paper does build further on the finding that irradiation is a non-enzymatic way to alpha-hydroxy-NMOR, when conjugated with phosphate or acetate this gives a fairly stable direct acting mutagen (in vitro, absence of enzymes avoids that alpha-hydroxy O-conjugated NMOR gets decomposed fastly).
For the enzymatic pathway: NMOR is metabolized mainly via alpha- and
beta-hydroxylation (O-conjugation as always a possibility). The hydroxylation product of NMOR is unstable and decomposes quickly to react with biological molecules, including DNA, resulting in further decomposition products. But alpha-hydroxy NMOR is effectively a shared “metabolite” photo-route and enzyme-route. So basing risk assessment for medicines on alpha-hydroxy NMOR enzyme-route can still be justified and in reality for the medicine exposure route if applicable, enzymes will not be equally suppressed (whereas mechanisms for UV protection can also play).
It is not because the photoactivation pathway could replace (cf. suppression of enzymes in experiments needed to see the effect) in vivo the role of enzymes (as seen by the in vivo micronucleus test with enzyme suppression but photoactivation), that the “metabolites” causing the effect are different. This helps to explain why this 2024 paper stresses the importance of environmental risk assessment for nitrosamines, as in the environment NMOR can be activated to a direct acting mutagen (like premetabolised) under the influence of irradiation. It also explains why the authors are focused on the stability of irradiation activated mutagenicity of NMOR in absence of enzymatic activity. Irradation risk on the medicine or its precursors directly (transforming NMOR impurities when present (and allowing conjugation)) is probably uncommon and in vivo this mechanism is clearly in competition with the enzymatic routes.
The 2024 paper does not move away from the theories on alpha-hydroxy and conjugated NMOR (similar NPIP). (I do recognise irradation-based “metabolites” of nitrosoproline are significantly differently as described in literature, cf. anchimeric assistance of COOH, and that you might still be doing a deep dive in the vast amount of research on this topic. In fact the (even in vitro) differences NMOR vs. NPRO already show that this is not one-shoe-fits all and that NMOR can’t be easily extrapolated to many NDSRIs).
I believe data generation is as important as hypothesis building, but that also hypothesis building should depart from available data and is thus dependent on data interpretation, which is where we are lost in translation (next to a few other things, like DNA alkylation risks linked to nitrosamines that are evaluated is broader than methylation).
I think this will also helpful.
180424_ACT-2023_Poster440-1.pdf (1.4 MB)