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A Study of Genotoxic and Secondary Mechanisms of Riddelliine Carcinogenesis


<ol> <li>To study the mechanisms of direct-acting genotoxicity (involving exogenous DNA adduct formation) of riddelliine.
<li>To analyze riddelliine-derived DNA adducts in target tissues of rats treated with riddelliine as part of the NTP chronic study, and from male and female rats to be treated at the NCTR for a shorter period of time with riddelliine and its reactive metabolite, dehydroriddelliine.
<li>If a dehydroretronecine-modified DNA adduct is detected in the liver tissues of animals treated with riddelliine, propose to determine whether or not this DNA adduct is also formed in animals treated with other tumorigenic pyrrolizidine alkaloids.
<li>To compare the metabolic activation pathways and DNA adduct formation of the tumorigenic pyrrolizidine alkaloid, riddelliine, retrorsine, and monocrotaline, and a non-tumorigenic pyrrolizidine alkaloid, retronecine in rat and human liver microsomal systems.</ol>

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FY 2000 Accomplishments: <ol> <li>A 32 P-postlabeling/HPLC method was developed for the identification and quantification of dehydroretronecine (DHR) DNA adducts.
<li>Synthesized dehydroretronecine and dehydroretronecine-modified dG-3'-phosphate adducts.
<li>Using this methodology, eight DHR-derived DNA adducts were detected in the livers of female rats treated with riddelliine.
<li>Two of the adducts were identified.
<li>Two manuscripts have been submitted.</ol>
FY 2001 Plans:<ol> <li>Continue characterization of dehydroretronecine DNA adducts.
<li>Compare and quantify riddelliine-derived adduct levels in target and non-target tissues of F344 rats and B6C3F1 mice.
<li>Conduct human microsomal metabolism studies with riddelliine.
<li>Determine the role of riddelliine N-oxide in riddelliine carcinogenesis.</ol> </p>

Harris, Angela
DHHS/FDA - National Center for Toxicological Research
Project number