April 18, 2008

Tobacco normally produces nicotine, a compound best known for its addictive properties. Nicotine is not a carcinogen, but through a process known as conversion, tobacco plants will metabolize nicotine molecules into another, potentially dangerous alkaloid. Scientists at University of Kentucky have identified the gene responsible for tobacco conversion and, in the process, learned a great deal about the molecular changes that occurred during the evolution of alkaloid composition of domesticated tobacco.

Alkaloids frequently serve as natural insecticides in plants. Balazs Siminszky, assistant professor in the College of Agriculture Department of Plant and Soil Sciences, working with UK postdoctoral Research Associate Lily Gavilano, in collaboration with researchers at North Carolina State University and with funding from Philip Morris USA, unraveled some of the mysteries behind the conversion of nicotine into a secondary alkaloid called nornicotine. This is relevant because as tobacco cures, nornicotine can be metabolized into a potent carcinogen known as NNN, nitrosonornicotine.

This research is part of the ongoing struggle to reduce the risk in smoking or chewing tobacco. However, lest smokers begin to breathe easily and think there’s a healthy tobacco on the horizon, Siminszky offered a word of warning, noting that more than 60 cancer-causing compounds have been found in tobacco smoke and at least 16 in unburned tobacco. His study looks at only one of those carcinogens.

One strategy to reduce NNN in air-cured tobaccos, where the conversion is more likely to occur, is to reduce the level of nornicotine in the plants. Siminszky said, though no one has an exact number, sometimes 15 to 30 percent of plants will convert to nornicotine-producing plants.

“The problem with the nornicotine-producing trait is that it occurs unexpectedly,” he said. “If you transplant tobacco derived from completely normal, nicotine-producing parents, some of the plants of the new generation will likely contain nornicotine-accumulating individuals.”

The study’s findings can have broad biological implications, because the genetic changes uncovered in this investigation may represent an example of processes that play a fundamental role in plant, animal and human genetics.

A screening process currently used by tobacco breeders has already contributed greatly to the reduction of nornicotine production in tobacco. Breeders routinely perform a chemical analysis of seed-producing plants to determine whether the parent plant accumulates nicotine- or nornicotine in the cured leaves. If a plant produces nornicotine, the breeder culls it and will not collect its seed.

“The problem is this particular method of eliminating nornicotine-producing plants is not perfect because tobacco conversion happens in a single generation,” Siminszky said. “So the current system is expensive because it takes all this effort for the breeders to screen, plus it’s imperfect.”

Siminszky and his team chose an alternative method for eliminating tobacco conversion. In collaboration with NC State researchers, the UK team isolated the culprit gene responsible for nornicotine production and devised a strategy to suppress its activity.

“Suppressing the gene resulted in reducing the plant’s nicotine-to-nornicotine conversion to less than 1 percent, even in plants that were genetically prone to nearly 100 percent conversion,” he said. “These plants were tested in the laboratory and the field, and we determined that they converted less than one percent nicotine to nornicotine. The field tests also show that compared to commercial tobacco, these plants produced six-fold less NNN, the carcinogen that we really wanted to reduce.”

Siminszky pointed out that lowering the rate of nicotine conversion in the transgenic plants to less than 1 percent was impressive because even a normal nicotine-producing tobacco plant will contain approximately 5 percent nornicotine content.

“Our transgenic plants are really producing even less nornicotine and NNN than the so-called nonconverter and nornicotine-free plants,” he explained. “This six-fold reduction in nornicotine and NNN contents actually is compared to the normal, nonconverter tobacco, not compared to converter tobacco. Compared to that we have many, many fold more reduction.”

The modified tobacco is not yet on the market and even if it were, Siminszky warned people not to get too excited.

“Nobody wants to give the message to people that now we’ve solved the cancer problem. That’s not true at all,” he said. “All we are saying at this point is this particular carcinogen has been reduced.”

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