By David N. Leff

Although they've dipped on the charts the last 10 years or so, the No. 1 serial killers of men and women in the U.S. are still heart attack and stroke.

This year, a predicted 1.5 million Americans will suffer a new or recurrent heart attack, and half a million of them will die of it.

Among the top 10 perpetrators of cardiovascular mortality, cigarettes rank high on the list of epidemiological risk factors, to wit: high blood pressure, high cholesterol, cigarette smoking, diabetes, obesity, male sex, familial early atherosclerosis, physical inactivity, advancing age, and type A personality (the stressed-out Type A vs. laid-back B individual is still controversial as a cardiovascular risk factor).

The etiological connection between inhaled tobacco smoke and lung cancer is pretty obvious. But what's smoking's causative link to heart attack?

Cigarettes don't act alone as a prime perpetrator of heart disease; they interact with some of the other nine risk factors, particularly item No. 2 (high cholesterol), by aggravating their effects.

Biochemist Anthony Cerami, who is a board member and principal scientific advisor to Alteon Inc., in Ramsey, N. J., has zeroed in on the toxic chemicals that form in tobacco smoke. Among them, he found, are certain reducing (i.e., reactive) sugars and other products that can react, sans benefit of enzymatic action, with proteins, lipids and nucleic acids, in a process called glycation.

He named these diverse compounds "advanced glycation end-products" (AGEs), which showed up in atherosclerotic vascular disease and DNA mutations.

In the current Proceedings of the National Academy of Sciences (PNAS), dated Dec. 9, 1997, Cerami reported that "tobacco smoke is a source of toxic reactive glycation products."

He pointed out in that paper, of which he is the senior author, that "although the chemical structures of only a few AGEs that form in vivo have been determined," food chemists describe them as forming during the cooking, processsing and long-term storage of foodstuffs. A French chemist first noticed this little-understood, enzyme-less Maillard reaction (a.k.a. the browning reaction). It occurs during heat exposure of carbohydrates and proteins, and accounts for the surface darkening of bakery products and meats. It ends typically with formation of the industrial chemical furfural.

"Food chemists continue to study Maillard reaction products intensively," Cerami pointed out, "as they are responsible for much of the flavor and aroma of cooked foods."

He reasoned that the curing of leaf tobacco must also involve the Maillard reaction and its effects. In the curing process, tobacco growers expose leaves to high temperatures (37 to 65 degrees Celcius) to reduce their moisture content and convert starches to reducing sugars, then age them for one to five years to remove odors and improve smoking quality.

Such curing, Cerami suggested, would make tobacco products "a significant source of reactants capable of promoting AGE formation, and thereby provide a possible mechanism to explain the high prevalence of atherosclerotic vascular disease and cancer in smokers."

"The normal function of AGEs," explained biochemist Carla Cerami, the PNAS paper's first author, "is as a marker that people and plant biomass are getting older. As anything ages, it gets more and more AGEs on it. Clinically," she pointed out, "there is a use for them."

AGEs are higher in diabetics, she said, "because they have a higher level of glucose in their blood all the time." (See BioWorld Today, Feb. 14, 1997, p. 2.) "So there's a common test — the glycosylated hemoglobin, or HbA1c test — that physicians use to monitor a patient's plasma glucose control during the preceding one month, so they don't get that many AGE products forming throughout their body."

HbA1c is produced by the nonenzymic glycosylation of the hemoglobin beta chain by plasma glucose; that is, it's an advanced glycation end-product. "My father, Anthony Cerami, developed the test some two decades ago," Carla observed.

Smokers Mimic Diabetic-Like Complications

"To pinpoint the glycation products in tobacco smoke," she recounted, "we took smoke from cigarettes, reacted it with protein, and used antibodies to detect the AGE molecules.

"In addition, we took Salmonella typhimurium bacteria, commonly used in the Ames test for carcinogenicity, and incubated them with regular cigarette smoke, and smoke from which we'd removed the glycation products. By measuring differences in mutation rate, we showed indirectly that the AGEs bind to and react with the bacterial DNA, thereby causing mutations."

Alteon, Cerami mentioned, "owns the rights to this cigarette technology."

Anthony Cerami added: "There are a lot of these reactive sugars in cigarette smoke; that's really quite dramatic. I think that took us all by surprise, and the fact that they actually volatilize in the smoke when you light a cigarette.

"Basically," he pointed out, "what happens is that a normal person is in effect converting himself into the amounts of glycation that you would find in a diabetic patient. And the complications that you see frequently in diabetes occur in smoking — peripheral vascular disease, atherosclerosis, strokes and so on. It really shows the commonality of these reactive sugars at promoting those kinds of damage in the body." *