The tissue levels of coenzyme Q1o (CoQ10) in endomyocardial biopsy samples and blood from 43 patients with cardiomyopathy were determined by steps of extraction, purification, and HPLC. The biopsy samples were obtained from the patients after a routine heart catheterization. Six pa-

No abstract

Coenzyme Qio (CoQ1o), a biochemically established redox component of respiration including the coupled mechanisms of electron transfer and oxidative phosphorylation, is naturally present in the human myocardium. A double-blind and double-crossover trial has been conducted by administering CoQ1o and a matching placebo orally to two groups of patients having class I or IV cardiomyopathy (classification according to criteria of the New York Heart Association

1. The metabolism of orally-administered sodium selenite and five methylated selenium compounds was investigated in the female rat at dosages equivalent to those used in other studies for prevention of mammary cancer. Dimethyl selenide (DMSe) exhaled within 24 h following dosing was measured, along with inorganic and monomethylated (MMSe) forms of selenium plus trimethylselenonium ion (TMSe+) in urine. 2. MMSe was the dominant metabolite of selenite given at low levels (0.1 ppm in the diet), but excretion of DMSe and TMSe+ increased sharply when selenite dosage was increased to the chemopreventive range of 3 ppm dietary Se. When similar chemopreventive levels of mono-, di-, or trimethylated compounds were administered, the total quantity of methylated metabolites was greater than for selenite and the metabolite profile reflected the expected point of entry into the intermediary metabolism pathway; the major metabolites were MMSe from Se-methylselenocysteine, DMSe from selenobetaine methyl ester, and TMSe+ from selenobetaine. However, the profile of metabolites provided clear evidence that the methylated selenium compounds underwent demethylation, as shown by the excretion of inorganic and MMSe. Selenium administered as dimethyl selenoxide was almost completely excreted and about 90% of the dose was recovered as DMSe, indicating that reduction was the major pathway. For TMSe+, about 10% of the dose was excreted as DMSe and 84% as TMSe+. 3. A low, non-toxic level of sodium arsenite (5 ppm As in the diet) that is known to modify differentially the anticarcinogenic activity of selenite and methylated selenium compounds did not modify the excretion of the methylated selenium metabolites. 4. It is concluded that high anticarcinogenic activity is associated with extensive excretion of methylated Se excretory metabolites, but high output of such metabolites per se does not necessarily lead to anticarcinogenic activity. The whole animal has extensive capabilities for interconverting forms of selenium, and retains significant amounts in tissues, complicating the interpretation of Se metabolism and anticarcinogenic action. Further research is needed on the forms of selenium present in tissues.

Recently El-Bayoumy and coworkers have reported that 1,4-phenylene-bis(methylene)selenocyanate (p-XSC) was very effective in inhibiting 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis and adduct formation during the initiation phase (Cancer Res., 52, 2402-2407, 1992). Furthermore, this compound was found to be well tolerated by rats at high doses. The present study was designed to extend these earlier observations by investigating the response to lower levels of p-XSC given either before or after DMBA administration. At a level of 15 p.p.m. Se, p-XSC suppressed total mammary tumor yield by 80% and 52% in the initiation phase and post-initiation phase, respectively. A dose-response effect was evident in the range 5-15 p.p.m. Se. When p-XSC was given at a level of 5 p.p.m. Se during the entire course of the experimental period, total tumor yield was reduced by half. This dose is about 4 x less than the maximum tolerable dose (MTD). Other selenocyanate analogs were also examined in an attempt to obtain information on their respective chemopreventive index, which is calculated as the ratio of MTD to the effective dose which produces approximately a 50% inhibition in total tumor yield (ED50). The reagents studied included potassium selenocyanate, methyl selenocyanate and benzyl selenocyanate, as well as sodium selenite (reference compound). Compared to p-XSC, which has a chemopreventive index of 4.0, the other four compounds have a lower index ranging from 1.3 for sodium selenite and potassium selenocyanate to 2.0 for methyl selenocyanate and 2.5 for benzyl selenocyanate. A high chemopreventive index signifies that a compound is well tolerated at doses required for cancer suppression. The last component of the present study involved the repletion assay of liver glutathione peroxidase in selenium-deficient rats as a biomarker to estimate the metabolizability of the above selenium compounds. The bioavailability data suggest that the selenium from p-XSC is not as efficiently incorporated into glutathione peroxidase as the selenium from selenite or the other selenocyanate analogs. Currently, we are working under the hypothesis that the chemical structure of the RSeCN compound could affect activity per se and also influence the rate of release of selenium from the parent compound, thereby impacting on the anticarcinogenic efficacy, tolerance and bioavailability of the compound.