Niacin Analogues

Tobacco products are considered to be predisposing factors in several forms of cancer. According to the American Cancer Society, there are 43 carcinogenic substances in tobacco smoke, and nicotine makes the use of tobacco products addictive. Smokeless tobacco (plug or leaf chewable tobacco or snuff) is considered to be a predisposing factor in oral cancers (US Surgeon General, 1986). Cadmium and nickel also have been inplicated in the carcinogenicity of tobacco products.

Since removal of tar by filters and the use of smokeless tobacco do not eliminate the risk of cancer associated with tobacco, the question remains "What are the components of tobacco most responsible for the increased risks of cancer?" One obvious possibility from our perspective is nicotine, itself, for its potential to interfere with monooxygenase-catalyzed reactions in about five ways:

Nicotine is a known substrate of this monooxygenase, so this non-nutritive compound can interfere directly with oxidations of regulatory substrates catalyzed by this enzyme.
Nicotine is also a close structural analogue of nicotinamide and has the potential for depleting NADPH by competitively inhibiting the absorption and incorporation of the vitamin.
Theoretically, nicotine can also interfere with the production and redox recycling of NADPH from NADP+, NAD+, and NADH.
In addition to the possibility of causing metabolic losses of NADPH, nicotine may compete directly with NADPH for the monooxygenase and other critical regulatory enzymic activities Consistent with this inhibitory potential is the observation that porcine liver monooxygenase catalyzes the oxidation of nicotine at a saturated maximum rate that is only 60 to 67% of that reported for good substrates for this monooxygenase.
Finally, any depletion of NADPH by nicotine described, supra, can result in an additional irreversible inactivation (kill) of the monooxygenase by normal body temperatures. The monooxygenase is highly vulnerable to thermal inactivation under two very interesting circumstances: 1) when deprived of NADP+ and especially NADPH, or 2) when deprived of oxygen in the presence of NADPH. The latter condition may exist in the center of rapidly growing tumors.

There is no question that metabolites of nicotine are carcinogenic and that nicotine itself is a cancer promoter in laboratory animals. Some human lung cancer cells that normally double every three days in cell culture will nearly triple over this same time period if nicotine is included in the medium. Though a gross oversimplification, it is an ironic coincidence that the maximum velocity for nicotine is a little less than two-thirds that of other substrates for the monooxygenase (supra) and that the growth rate of some cancer cells is three-halves as fast when nicotine is present in the culture medium. Let's see if linking observations by four different researchers about nicotine and carcinogenesis and the monooxygenase lends substance to this assertion and, at the same time, drives a message home:

Nicotine, the addictive substance in tobacco products (even the pinch-between-the-cheek-and-gum, smokeless kind), promotes tumor induction with DMBA in the cheek pouch of hamsters; nicotine cause the numbers of small tumors produced by DMBA to more than triple, the numbers of medium-sized tumors to more than double, and even greater increases in numbers of large tumors.
An endogenous substrate for the monooxygenase, cysteamine, protects against the carcinogenesis with DMBA, possibly by sacrificial protection of the vitaletheine modulators.
Substrates for the monooxygenase that do not resemble the vitaletheine modulators are often carcinogenic; cysteamine is part of the base structure for the vitaletheine modulators.
In addition to being carcinogenic, DMBA nearly eliminates the hemolytic plaque response; the numbers of immune cells that can produce protective cytolytic antibodies when challenged are diminished 95% or more by DMBA.
Vitalethine stimulates the production of protective cytolytic antibodies, treats cancer, and is suspected of being an endogenous substrate for the monooxygenase.
A survey of the literature indicates that the hemolytic plaque response is often linked inversely to carcinogenesis, especially when the investigative agent affecting the antibody producing cells is not overtly cytotoxic toward and does not directly affect the proliferation of immune or tumor cells; under these circumstances, agents that stimulate the plaque-forming (cytolytic antibody) response typically protect against cancer, whereas those that inhibit the production of these cytolytic antibodies (like the agents, DMBA and MMI) promote the development of tumors. It is interesting that MMI is a conjugated thiol and one of the best substrates for the monooxygenase, but this is where the similarities with cysteamine and the vitaletheine modulators end; MMI uncouples hemolytic plaque responses and other important biological processes (such as the production of thyroid hormone), whereas cysteamine and other metabolites in the Coenzyme A pathway increase iodide incorporation and stimulate immunological responses.

An interesting general feature about the regulation of biological systems is that minor inhibition at any one step in a regulatory cascade (10% here, 10% there) can be amplified by multiple affected sites along the entire pathway to produce dramatic inhibition at the endpoint. The potential for cascade-amplified inhibition of the monooxygenase with nicotine clearly exists. If nicotine proves to be a predisposing factor through this proposed mechanism, nicotine patches will solve a tobacco consumer's risk for cancer only if used to completely end the addiction.

GO TO:

Home	Overview	People	Journal	Nutrition
Environment	Treatments	WWW Links	Outline	e-mail us