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Housecleaning cells may become assassins.

Four years ago, scientists reported that in rats, large doses of vitamin A transform minimally toxic doses of carbon tetrachloride into a potent liver poison. Because the vitamin by itself exhibited no adverse liver effects, the researchers began investigating to find the agent behind vitamin A's lethal action.

Last week, they unmasked the villain. And in classic murder-mystery fashion, they show that Kupffer - the "butler" -- did it.

Named for 19th century anatomist Karl W. von Kupffer, these liver residents form an integral part of the immune system. Like other macrophages, Kupffer cells remove unwanted visitors -- such as bacteria and parasites -- by engulfing and chemically destroying them. They also rid their domicile of foreign debris.

Like any good butler, they wait quietly until called upon. Only when summoned to action do they show force. It now appears that the pent-up chemical fury they harbor can, once unleashed, compound the liver injury they had been mobilized to prevent, notes I. Glenn Sipes of the University of Arizona in Tucson.

Three reports of vitamin A's potentiation of liver toxicity by his team appear in the April TOXICOLOGY AND APPLIED PHARMACOLOGY. Two other reports in the journal also characterize this Jekyll-to-Hyde transformation by Kupffer cells.

Rats exposed to a single minimally toxic dose of carbon tetrachloride (0.15 milliliter per kilogram of body weight) exhibit a small amount of damage in key cells in the liver, known as hepatocytes. Sipes and his co-workers compared that damage to what they saw in animals who received up to 250,000 international units of vitamin A (retinol) per kilogram of body weight daily

In animals pretreated with vitamin A for one day to five weeks prior to carbontetrachloride exposure, Sipes says, "the previously minimal injury has exploded to look like we've given a huge dose of carbon tetrachloride." Vitamin pretreatment did not affect the type of cell affected or region of injury, only the magnitude of damage.

In similar tests, rats received toxicantsacetaminophen, allyl alcohol, and a poison produced by E. coli bacteria- which caused very different patterns of liver damage. Again, pretreatment with vitamin A exaggerated the specific pattern of damage characteristic of each agent.

Sipes recalls being puzzled about why systemic delivery of the vitamin should foster selective damage only to those cells targeted by another toxic chemical. Eventually, members of his team spotted structural changes in Kupffer cells from vitamin-A-treated rats. The changes signaled the Kupffers were primed to release biologically damaging free radicals.

So Sipes' team performed their experiments again. But this time they added one of three different chemicals to shut down Kupffer-cell activation. And each time vitamin A's exaggeration of carbon tetrachloride's toxicity disappeared. Concludes Sipes, "Small amounts of carbon tetrachloride somehow triggered primed Kupffer cells to over-respond" in their production of cell-killing free radicals.

"We got into these studies because large doses of [vitamin-A-like] retinoids are being used in cancer therapy," Sipes says. Future studies will explore whether lowering doses of both the vitamin (to levels more commonly consumed by humans) and a toxic chemical also causes damage.

But the biggest take-home message, Sipes says, is the value of animals in studying potentially toxic mixtures. Popular in vitro tests using only one type of cell would miss this new effect, he says, since the toxicity depends on the interaction of different cell types.

Though such research into the effects of chemical mixtures "is really at an embryonic stage," it is essential for teasing out risks people face from exposures to a complex cocktail of agents in the real world, points out Raymond S.H. Yang of Colorado State University in Fort Collins.
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Title Annotation:Kupffer cells
Author:Raloff, Janet
Publication:Science News
Date:May 1, 1993
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