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" Nicotine is metabolised to several products but
only with cotinine, the hypothetical hydroxy nicotine and the oxides-of
_ . . - , ... __., . .. . _.: ~...
. t «~"~.qZ 7Lf ~,r1,9 a~a:~~ < s .5:..4._:7k
Cotinine is an important metabolite of nicotine. Truhaut, de Clercq and
Loisillier (1964) showed that cotinine was 50 times less toxic than nicotine on
injection in mice. When administered to 60 rats in the drinking water 12 out of '
15 that died between the 8th and.18th months had various malignant tumours but
none of the 45 rats which were killed after 18 months had malignant tumours.
SchmUhl and Osswald (1968)'treated 60 rats with cotinine so that they
received~ doses of about 20g. per Kg. body weight. One rat developed a hepatoma
but the incidence of fibromas and thymomas was the same as in the control animals.` .
When tragated in adult mice by subcutaneous injection or skin painting cotinine
did not induce any tumours.' On.inj,ection.into newborn mice or implantation into
_ cot'inine is a rnaj or metabolite of 'nictoine it
by adult and foetal human lung.
H dy roxynicotine
:Metabolism and Nitrosation of Nictotine
hydride does protect against nicotine.
could not be obtained in a'pure state.
Ys : `r a
---the bladders'of adult mice it induced some tumours (Boyland, 1968 ) . d
obsem-f~s). The evidence that cotinine is carcinogenic is not conclusive but as
shouYd'investigated further in long'
term tests. Cotinine is formed from nicotine by the lung,tissue of rats and also
The experiments indicate that'this
When rats are pretreated with nicotine they became resistant to the lethal
action of'nicotine. This could be due to a nicotine metabolite protecting the
animal,p from the effects of nicotine itself. Cotinine does not have the protective
effect but a product prepared by reduction of cotinine with lithium aluminium
The product.,,which could be hydro.cy. nicotine,
~ ~r ~..
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hypothetical intermediary metabolite could be the compound that reduces'the
The pyrolidine -
in small amounts
steJo isomers of
. .- . ' .~ _
nicotine-N-oxide can be separated by chromatography and both are formed on
in tobacco and are £ormed by metabolic processes.
oxidation by the liver and lung and are excreted in urine (Booth and Boyland,
a tertiary amine~reacts-with nitrous acid rapidly
is a potent carcinogen (Boyland.and Walker 1974 a
(Hoffmann, Rathkamp and Liu, 1974). In
more rapidly.than nitrosonornicotine is
be the conversion of nicotine to nornicotine.
(Boyland, Roe and Gorrod, 196!+).
, . . _ , : .. , : ..
The relative amounts of the D and f-isomers produced vary with different
The- 7 - N - oxides of xanthine and guanine are carcinogenic on injection
By analogy the N'- oxides of.nicotine.could be carcinogenic.
Although the old text books of organic chemistry indicate that tertiary
amines are not nitrosated more recent research has shown that many tertiary'amines
react with nitrous acid to yield nitrosamines. The analgesic aminopyren e!,which,is
to give dimethylnitrosamine, which
the reaction nicotine disappears much
slowly nitrosated. Nitrosonornicotine,is carcinogenic when injected into mice
Although th e reaction with nitrous acid isslaw nitrosonornicotine
nitrosamines occur in cigarette smoke. The known nitrosamines present in the smoke
of one American cigarette amount to about 250ng. By smoking 30 cigarettes each
day for a year (10,000 cigarettes) a smo'~cer would inhale 2.5mg of known nitr©sami:nes
There could be other nitrosamines present that have not been identified.
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This could be because the less alkaline smoke of British cigarettes is more easily
.The formation of nitrosamines could be much greater in British cigarettes
because the smoke of.these is more acid than that of American and European
. . _.;~,. ~ . ... _ . . _ ~
cigarettes (Elson, Betts and Passey, 1972).` British cigarettes appear to be more
active in causing lung,cancer than those of other countries (Elson and Betts, 1972).
inhaled but it could be because the amounts of nitrosamine.s formed in the cigarettes`
-.: . . .°. f
. . . ~. , . . . . . . ~ v>>~`.: _ f
amine, the square of the nitrous acid concentration, the pH and the presence of
. .. . . . .. . . 1. 'R 1.
catalysts. The concentration of the amine nicotine in cigarettes is high. The
optimum pH of the reaction is about 3.5 so that it proceeds much more rapidly at
pH 4.(the pH of smoke of British cigarettes) than at pH 5 (the pH of American
The rate of formation of nitrosamines depends upon the concentration of the
catalysed by thiocyanate (Boyland and Walker,~ ;
1974 b). Thiocyanate occurs in some vegetables and is formed in the body.and
excreted in saliva and in urine. The saliva of smokers contains much more Q
thiocyanate than that of non-smokers. Smoke contains some cyanide which is
converted to thiocyanate in the body) but smoking increases the concentration of j
thiocyanate in saliva either by stimulating secretion in saliva or inhibiting
, _ . , ..
secretion by the kidney. Thiocyanate increases the formation of nitrosamines in the
Nitrosamines tz'h~~ be important carcinogens-in smoke. The amount present
acid conditions of the stomach. Smoking couLd increase the incidence
through this mechanism which may be due to nicotine.
could be reduced by reduction of the amount of nicotine present, oxides of
nitrogefi formed and of acid formed on burning. The amount of acid present in smoke
depends on the carbohydrates present in the tobacco and is much less iY air-cured a
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Booth, J, and Boyland,
.. . :L.:
. (1971). Biochem. Pharmacol. 20, 407.
. (1968). Planta Medica~Supplement. p13.
. '.. J .., t t
.. : _.. .
~ - . . ~`S . ~'r-,r:'7 . u' .. , ~ . , . ~ . .. . - . ~ ~ .. .. .. ._ . . . r t ..... ": F
. (1974 a)'. Arzneimittel-forsch.
. :(1964), hature. 202, 1126 . t
;Boyland, E.,'Roe, F,J.C. and Gorrod, J.W,
Boyland,+E. and Walker, S.
=.Boyland', E. and Walker, S.A. (1974b). Nature, 248, 601.
~~-:.,.F_ . . . . .
. . . r. y"',' . . ... . ... ~ .. ~ . ., . _ . , ,..
Elson, L.A. and Betts, T.E.
(1972)'. J. Nat. Cancer Inst., 48, 1885.
Elson, L.A,,Betts, T.E., and Passey, R.D. (1972). Fnt. J. Cancer. 9,666-675.
Hoffaan, D., Rathkamg; C. and Liu, Y.Y. '(1974).` In press.
,., . .
Schmahl, D. and Osswald, H. (19b8). Z. Krebsfursch. 71, 198.
--*-1'ruhau-t, R. ; - C-lercq, -M.-- de . and-Loisiller,.
. = (1964) : Path. Biol.', 12, 39.