Carcenogenicity of certain secondary and tertiary amines via N-nitroso derivatives.

[atara]

This is kind of an educated guess, so using it to predict that something is or isn't carcinogenic would be pretty dumb.

Nicotine and nornicotine react with nitrite in saliva to produce the derivative N-nitrosonornicotine.

http://en.wikipedia.org/wiki/N-Nitrosonornicotine

And, since N-nitrosoamines are, as a class, carcinogenic, I'm beginning to wonder if this compound isn't responsible for most of the toxicity of tobacco and tobacco products. Reason being, tobacco is carcinogenic chewed as well as smoked, so I find it hard to believe that the combustion products of nicotine are the culprits. Dip is carcinogenic. Cigars are, too. Even clean tobacco is carcinogenic.

Further, chewing areca nut is carcinogenic. Arecoline is also a tertiary amine with an easily-removed methyl group:

http://en.wikipedia.org/wiki/Arecoline

...and I'd guess that N-nitrosonorarecoline is generated from the chewing of areca nut in much the same way that N-nitrosonornicotine is generated from chewing tobacco.

The assumption is that the frequent use, sublingually or smoked (but not by other methods), of any compound with a secondary amine or a methylated tertiary amine, is going to be carcinogenic via a conversion to an N-nitroso derivative. This includes cocaine, methamphetamine, and morphine, but it does not include kratom (indoles are not amines), cannabis, khat, or salvia.

It theoretically includes MDMA, but MDMA is never smoked or chewed, and it theoretically includes LSD, but doses of LSD are a hundred times smaller than doses of morphine, nicotine, cocaine (only as crack cocaine), or arecoline, and presumably a hundred times less carcinogenic; further, LSD is never used "frequently". And yes, it includes DMT, if used "frequently" (but I think you'd have bigger problems!).

Is this a reasonable hypothesis? It's consistent with the data, at least in the cases of tobacco, areca nut, cannabis, and khat.

The problem is, secondary amines are just so pervasive, it's hard for me to imagine faulting them for so much. Perhaps there's an additional requirement, that the drug be acidic, so as to activate the nitrite.

EDIT: apparently I can't spell "carcinogen". Bah.

EDIT: Actually, it looks like khat may be carcinogenic, though there's very little data -- all of the studies I found reported high rates of concomitant tobacco use.

One potentially telling prediction: if this is true, nicotine gum should also be carcinogenic.

 

[wungchow]

IIRC, the amine needs to be attached to an allylic carbon (or benzylic, etc) in order for any significant quantity of the nitrosamine derivative to form...

 

[atara]

IIRC, the amine needs to be attached to an allylic carbon (or benzylic, etc) in order for any significant quantity of the nitrosamine derivative to form...

Huh. So that applies to arecoline, ergine, thebaine, and nicotine, but not to morphine, cocaine, or amphetamines; in particular it means that opium would be worse than its derivatives due to the presence of thebaine.

 

[rnd.id.]

From the first article you linked:

NNN is produced by the nitrosation of nicotine during the curing, ageing, processing, and smoking of tobacco. Roughly half of the NNN originates in the unburnt tobacco, with the remainder being formed during burning.
[...]
Some of the NNN present in the saliva of tobacco users is produced endogenously from nitrite in saliva and tobacco alkaloids including nicotine.

(Emphasis added).

Also note that there's no source given for either statement (I have no reason to actively doubt it, though).

My point being that I don't think there's a reason to panic for nicotine gum users yet

Additionally, while tobacco is apparently carcinogenic in other ways than through its combustion products, AFAIK one of the most common and most deadly cancers caused by smoking is lung cancer, so I wouldn't be too quick to declare the combustion products as not (the bulk of the) culprits.

 

[fastandbulbous]

Technically N-nitrosoamines only form from secondary amines as the tertiary amines mentioned need to degrade to a secondary amine first. As far as I knew, all nitrosoamines are carcinogenic as in vivo the can react with a DNA base and turn the NH2 group into an OH group (nitrous acid & primary amines give an alcohol and nitrogen)

Mind you, saying that, if you eat a lot of cured/processed meats, they all contain potassium nitrite as a preservative, which becomes nitrous acid in the stomach. Add to that the proline content of some foods (the only common secondary amine amino acid) and you've got yourself a nasty little combination...