Clues to a new class of liver carcinogens
Peroxisomes are a curiosity. These round, dense constituents of plant and animal cells harbor enzymes to make and break hydrogen peroxide (H.sub.2.O.sub.2.). While it's unclear what beneficial role. If any, peroxisomes play in mammalian cells, new research suggests they can become the means by which one class of chemicals triggers the development of apparently novel liver cancers.
A number of potentially important chemicals -- including several powerful cholesterol-lowering drugs, herbicides and plasticizers -- are liver carcinogens that uniformly elude detection by short-term carcinogen-screening assays, such as the Ames test. The reason, explains toxicologist Janardan Reddy at Northwestern University Medical School in Chicago, is that the short-term screening tests look for chemicals that cause genetic mutations in bacteria. But the liver carcinogens he studies don't interact directly with DNA. Instead, they trigger the liver to produce peroxisomes -- 15 to 20 times the normal number.
These peroxisome-proliferating chemicals (PPCs) also activate a trio of genes inside liver-cell nuclei. Within minutes to hours of PPC exposure, the genetic trio stimulates a cell's peroxisome production of H.sub.2.O.sub.2.--to levels 30 or 40 times normal. Meanwhile, a peroxisome's H.sub.2.O.sub.2.-degrading enzymes will not even double.
Elevated peroxisome-H.sub.2.O.sub.2 concentrations, caused by this mismatch between its production and breakdown rates, eventually result in large quantities of the potentially toxic chemical diffusing into liver cells. …