While not technically nitrosamines from a pharmaceutical perspective, I found this a fascinating read.
Gut microbiota carcinogen metabolism causes distal tissue tumours | Nature
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Interesting article, but the conclusion seems to contradict the CPCA model.
In fact, if we apply the CPCA model to BBN and BCPN, we obtain:
BBN
Count of hydrogen atoms on each a-carbon [2, 2] and corresponding a-Hydrogen Score is 1
Score: 1. Potency Category 1 : AI = 18 ng/day
BCPN
Count of hydrogen atoms on each a-carbon [2, 2] and corresponding a-Hydrogen Score is 1
Carboxylic acid group is found, Individual Deactivating Feature Score +3
Score: 4. Potency Category 4 : AI = 1500 ng/day
While the authors affirms that:
Notably, N-butyl-N-(3-carboxypropyl)-nitrosamine (BCPN),
the oxidation product of BBN, induces tumorigenesis through DNA
adduct formation in the urothelium.
This means that BBN and BCPN have practically the same potency, because BBN is metabolized to BCPN. so the CPCA model fails when we consider also the probable metabolism of the nitrosamines?
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Interesting - I hadn’t considered applying the CPCA to the 2 molecules.
But does this indicate a possible weakness of the CPCA model, and potentially explain why some nitrosamines, which could reasonably be expected to be problematic, have started to show negative AMES tests? Does it also link with some of the quantum mechanics papers, and models looking beyond the initial formation of the nitrosamine and reaction with the CYP to the full (potential) fate of the diazonium and carbenium ions?
I don’t know the answers to these questions, the CPCA is a very good starting point, but I feel there are more discoveries ahead of us yet.
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This would match well with something that I’ve been saying for some time, but isn’t yet fully elucidated - we need to understand the full metabolic profile of the nitrosamine; while the a-carbon hydroxylation is facile it is definitely not the only thing that can occur, and these ‘side reactions’ can be, as in this case, detoxifying.
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For clarity, the limitation of CPCA in dealing with some COOH-containing nitrosamines which are known bladder carcinogens and the importance of toxicokinetics behind this (but always nice to see newer studies in Nature reconfirm this), is known by NITWG, it is not a model flaw NITWG was not aware about when launching the model. You will see this reconfirmed in the CPCA design paper NITWG recently published: Redirecting
Further perspective:
Figure BBN BCPN.pdf (132.3 KB)
BBN BCPN vs CPCA.pdf (215.6 KB)
The quantum mechanics papers mostly focus on the M from ADME, whereas for these cases the D and E is also a big part of the mutagenicity risk assessment. But it is true that a lot of in silico approaches do not focus too much on competitive metabolisation calculation, in some cases some do not fully calculate the alpha-hydroxylation based route but immediately jump to the in vivo correlation based on simplified calculation approaches. I believe it is the complexity of the case that determines the calculation strategy, which can be often be designed based on literature review and available data.