UC Systemwide Toxic Substances Research and Teaching Program

UC Toxics News: Fall 2003
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Exposure to benzene, an ubiquitous environmental contaminant, is known to greatly increase the risk of developing leukemia, a cancer of blood-forming cells in bone marrow. What is not known is the mechanism through which benzene causes leukemia. Scott Mondrala, a doctoral student and TSR&TP trainee in the Toxic Mechanisms Lead Campus Program at UC Riverside, is looking closely into how benzene and its metabolites affect cells in gene-environment interactions.

Scott Mondrala, TSR&TP trainee at UC Riverside, is investigating how benzene metabolites inhibit an enzyme during cell division, the mechanism that may be responsible for benzene-induced leukemia.

There are multiple sources of benzene in the environment – ambient exposure occurs commonly from gasoline and cigarette smoke. However, the highest and most dangerous exposures occur in industry, such as shoemaking and painting processes in Asia where workers are exposed to benzene-containing glues and solvents.

Benzene itself does not cause the problem. When inhaled, benzene is oxidized in the body into multiple metabolites – including hydroquinone, which can then be oxidized into 1,4-benzoquinone in the bone marrow. Mondrala is investigating how benzoquinone may interfere with cell division and DNA integrity through inhibition of topoisomerase II, a DNA manipulating enzyme.

Topo II allows the double helix of DNA to untangle during cell division so the chromosomes can replicate and segregate properly. Inhibiting topo II can cause cell cycle blocks and DNA breakage. And these DNA disruptions can lead to cancer. But, Mondrala cautions, "there may be a combination of mechanisms that ultimately results in leukemia."

Ironically, several chemotherapy drugs work by inhibiting topo II. Because topo II is involved in cell division, blocking it interferes with the rapid growth of cancer. "The topo II inhibitors used as chemotherapy drugs have been shown to be very effective against certain types of cancers such as testicular, breast, and lung," says Mondrala, "but, inhibition of this enzyme has also been shown to cause chromosomal mutations at specific genes." People who take some common topo II inhibiting drugs have shown a 2-12% chance of developing leukemia as a result. This link provides further evidence that inhibition of topo II is the mechanism Mondrala is looking for.

The first goal of Mondrala's doctoral research was to determine at which point the benzene metabolites inhibit topo II. In the enzyme’s catalytic cycle, there is a stage called the cleavable complex – that point in the catalytic cycle in which a transient double strand break is produced in the DNA double helix.. When a chemical inhibits the enzyme at this point, it is referred to as a topo II poison. Mondrala's research has shown that benzoquinone inhibits topo II outside of this stage, therefore it is a catalytic inhibitor of topo II. His second goal is to look at the binding of these metabolites to the enzyme and then he will confirm that the metabolites are catalytic inhibitors in cell culture.

Mondrala's research provides insight into the questions of gene-environment interactions such as why people who have been exposed to the same level of toxicants have dramatically different responses. In the case of benzene, metabolic differences can result in different risks of chromosomal mutations that might later develop into cancer.

Being a trainee of the TSR&TP has expanded Mondrala's knowledge of science, especially toxicology. "We all get focused on our little piece of science," he says. "It's nice to interact with people in different fields, and TSR&TP gives us that opportunity." Through TSR&TP meetings, Mondrala says he has become aware of a lot of techniques that will be useful in his own research. "It's been a positive experience. The more you have to explain your research, the more you are forced to understand it yourself".

 

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