Molinate: A Metabolic Explanation for Species Dif 96

Molinate: A Metabolic Explana- tion for Species Diferences in Susceptibility to Male Reproductive Toxicity-96
Project Leader and Principal UC Investigators Marion G. Miller, professor, Department of Environmental Toxicology, UC Davis Will Jewel, graduate student, Department of Environmental Toxicology, UC Davis Bruce Winder, postgraduate researcher, Department of Environmental Toxicology, UC Davis	Environmental toxicologists continued a second year of research on the toxicity of the rice herbicide molinate. Since the herbicide has been shown to cause toxicity in rats, concerns have been raised about its potential threat to humans. In the first year of the study researchers identified different metabolic pathways at work in humans and rats that may account for different toxicological responses. In vitro studies in rats strongly implicated a metabolite of molinate as the chemical species responsible for testicular toxicity. In the current year's work scientists determined that in order for this metabolite to exert its toxic action it must be metabolized in the liver. Since liver metabolism would play an important role in formation of the toxic metabolite, researchers examined the ability of liver enzymes from humans and rats to activate molinate with resultant formation of the toxic compound. Their observations could enable scientists to predict the likelihood of human toxicity (i.e. just how readily might humans form this metabolite?) The first year's research drew from in vitro samples from only one rat and one human preparation. Preliminary indications showed that humans have less ability to form toxic metabolites than rats. In 1996 toxicologists examined three rat preparations and seven human preparations. This study still indicates that at low dose levels humans form less of the sulfoxide compound leading to toxicity than do rats. However, researchers believe that at higher doses the sulfoxidation process would increase in humans. Human liver preparations showed wide variability in their metabolic capabilities, thus blurring species differences. The capacity of the human liver not only to form but also to detoxify the toxic metabolite is currently being investigated. Scientists suspect that if it reaches the testis, sulfoxide may bind with and inhibit an important enzyme involved in testosterone production. Attention is now focused on the chemical mechanisms directly responsible for this physiological response-and the likelihood of this occurring in humans.

Molinate: A Metabolic Explana-
tion for Species Diferences in
Susceptibility to Male Reproductive
Toxicity-96

Project Leader and Principal UC Investigators

Marion G. Miller, professor, Department of Environmental Toxicology, UC Davis

Will Jewel, graduate student, Department of Environmental Toxicology, UC Davis

Bruce Winder, postgraduate researcher, Department of Environmental Toxicology, UC Davis

Environmental toxicologists continued a second year of research on the toxicity of the rice herbicide molinate. Since the herbicide has been shown to cause toxicity in rats, concerns have been raised about its potential threat to humans.

In the first year of the study researchers identified different metabolic pathways at work in humans and rats that may account for different toxicological responses. In vitro studies in rats strongly implicated a metabolite of molinate Molinate1.jpg (83129 bytes) as the chemical species responsible for testicular toxicity. In the current year's work scientists determined that in order for this metabolite to exert its toxic action it must be metabolized in the liver. Since liver metabolism would play an important role in formation of the toxic metabolite, researchers examined the ability of liver enzymes from humans and rats to activate molinate with resultant formation of the toxic compound. Their observations could enable scientists to predict the likelihood of human toxicity (i.e. just how readily might humans form this metabolite?)

The first year's research drew from in vitro samples from only one rat and one human preparation. Preliminary indications showed that humans have less Molinate2.jpg (117821 bytes) ability to form toxic metabolites than rats. In 1996 toxicologists examined three rat preparations and seven human preparations. This study still indicates that at low dose levels humans form less of the sulfoxide compound leading to toxicity than do rats. However, researchers believe that at higher doses the sulfoxidation process would increase in humans. Human liver preparations showed wide variability in their metabolic capabilities, thus blurring species differences.

The capacity of the human liver not only to form but also to detoxify the toxic metabolite is currently being investigated. Scientists suspect that if it reaches the testis, sulfoxide may bind with and inhibit an important enzyme involved in testosterone production. Attention is now focused on the chemical mechanisms directly responsible for this physiological response-and the likelihood of this occurring in humans.