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of a prostanoid pathway does provide a mechanistic explanation for the reproductive effects observed in animals (see below).

Of the 15 reported cases of chaparral-associated hepatotoxicity, only one case was associated with ingestion of chaparral tea, whereas 11 cases were associated with ingestion of capsules or tablets containing chaparral. If NDGA contributes to the toxicity, it is important to note that it and other nonpolar compounds, including lignans, appear to be minimal in a water extract/tea in contrast to an alcoholic extract (Obermeyer et al., 1995). This differential extraction of lignans by water extraction versus alcohol extraction (Obermeyer et al., 1995) is explained by the lipophilic character of lignans. Therefore, alcoholic extracts of leaf or other aerial plant parts would contain larger amounts of NDGA and other lipophilic compounds than a water extract/tea.

Nephrotoxicity: There are no reports of renal damage following chaparral ingestion in humans or in relevant animal feeding studies. Toxicology studies of NDGA administration in rodents have repeatedly shown nephrotoxicity, including proximal tubular damage and cyst formation.

NDGA can be expected to be a substrate for cytochrome P450-dependent quinone formation based on its chemical structure, as well as on evidence discussed by Obermeyer and colleagues (1995). A plausible mechanism of cytotoxicity of NDGA is cytochrome P450-dependent metabolism of NDGA to a toxic quinone with failure to remove this reactive metabolite by conjugation if glutathione is limiting. It is possible that there is a link between the nephrotoxicity of NDGA in animals and hepatotoxicity of chaparral in humans based on the fact that both the renal proximal tubules and the liver are major sites of xenobiotic metabolism. A parallel finding has been demonstrated in rodents; both renal and hepatic toxicity develop in response to the toxic quinone imine from acetaminophen.

Reproductive toxicity: Since reproductive effects are less likely to be detected in humans, animal data deserve careful consideration. Reproductive toxicity has been demonstrated by one group studying chaparral administered to female rats and three groups studying NDGA administered to female rats or mice. The chaparral study identified anti-implantation activity while the NDGA studies identified inhibition of ovulation and increased resorption of fetuses. These data are supported by the findings that NDGA inhibits prostaglandin synthesis, cyclooxygenase, and lipoxygenases. Because of the important role of eicosanoids in reproduction and fetal development, inhibitors of prostanoid pathways are contraindicated during the first and third trimesters of pregnancy (Mikuni et al., 1998).



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