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).