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Many rat models of human chronic diseases (atherosclerosis, cancer, osteoporosis) have been used to assess the risk-benefit ratio of soy isoflavones. However, little attention has been paid to differences in isoflavone metabolism between humans and rats and hence the appropriateness of these models. In the present study, we have examined the composition and concentrations of isoflavones and their metabolites in serum and urine of rats fed a lab dry pellet diet containing soy supplemented with genistein (200 mg and 2000 mg/kg diet). Animals were fed the diets for 90 d. Total urine 72-h collections were made immediately before obtaining blood by cardiac puncture. Isoflavones and their metabolites in urine and serum samples were analyzed by liquid chromatography-multiple reaction ion monitoring-mass spectrometry. RESULTS: In rats on the unsupplemented diet, equol is present at 6-9-fold higher concentrations (2730 [+ or -] 283 nmol/L) than genistein (372 [+ or -] 88 nmol/L) or daidzein (307 [+ or -] 60 nmol/L). Diets supplemented with genistein led to dose-dependent increases in serum genistein concentrations (1182 [+ or -] 445 nmol/L at 200 mg/kg, 5352 [+ or -] 1126 nmol/L at 2000 mg/kg) without effect on daidzein or equol. In urine of rats on the unsupplemented diet, the output of equol (1849 [+ or -] 189 nmol/d) was similar to that of daidzein (2469 [+ or -] 375 nmol/d) and genistein (1772 [+ or -] 275 nmol/d). Diets supplemented with genistein led to dose-dependent increases in genistein output (4146 [+ or -] 146 at 200 mg/kg, 18287 [+ or -] 3574 nmol/d at 2000 mg/kg) whereas there were no significant changes in daidzein or equol output. Urinary clearance of equol (0.72 [+ or -] 0.13 L/d) was 11-fold less than daidzein (8.50 [+ or -] 0.54 L/d) and 7-fold less than genistein (5.16 [+ or -] 0.62 L/d). SUMMARY: These data revealed that rats, unlike humans, are equol dominant because of active renal excretion of daidzein and genistein but not equol.

The detection of telomerase activity has been proposed as a biomarker of breast cancer development and progression. In this study, we used cell proliferation and telomerase in MNU (N-methyl-N-nitrosourea)-induced mammary carcinomas as targets for assessing the response of tumor cells to 4-(hydroxyphenyl)retinamide (4-HPR), a known inhibitor of mammary carcinogenesis in animal models and premenopausal women. In mammary tumors of rats treated for 1, 2, 4 or 6 weeks with 4-HPR, we observed that telomerase activity decreased progressively with the extension of 4-HPR administration. A marked reduction in telomerase activity was already observed by 2 weeks after treatment and the lowest level was found at 6 weeks after initiation of 4-HPR treatment. The changes in telomerase activity were preceded and accompanied by a significant decrease in the percentage of proliferating cells as evaluated by 5-bromodeoxyuridine (BrdU)-labeling. However, when the values of telomerase activity in the individual tumors were compared with the percentage of proliferating cells, no significant correlation was found. These data suggest that the decreased telomerase activity in the animals treated with 4-HPR is not a simple consequence of the changes in cell proliferation, but a more complex phenomenon involving different cellular mechanisms and pathways. The time-dependent and consistent decrease of telomerase activity in the tumors treated with 4-HPR suggests that, in addition to the percentage of proliferating cells, telomerase activity could also be used as an endpoint in breast cancer chemotherapy studies. [ABSTRACT FROM PUBLISHER]

A wide variety of compounds was examined for the ability to induce a specific form of hepatic cytochrome P450 and to promote the development of DEN-initiated liver tumors (adenomas and carcinomas) in rats over a 72 week period. The induction of cytochrome P450b was determined indirectly by measuring the hepatic induction of pentoxy-or benzyloxyresorufin O-dealkylase activities, which are highly specific substrates for the major phenobarbital-inducible forms of cytochrome P450 in the rat.(10) Results in the rat showed: (1) potent inducers (> 40 ×) of P450b (i.e., phenobarbital, barbital, ethylphenyl-hydantoin, and DDT) are all potent liver tumor promoters; (2) structural analogs that are not inducers of P450b (i.e., hexobarbital, monoethylbarbituric acid, monophenyl-barbituric acid, and diethylhydantoin) all fail to display significant liver tumor promoting activity; and (3) the concomitant induction of liver hypertrophy, microsomal epoxide hydrolase, and cytochrome P450b appears to be proportional and argues for some coordinated “pleiotropic” response of liver parenchyma to these inducers. Additional studies showed that phenobarbital induced cytochrome P450b and was a liver tumor promoter not only in rats, but also in mice and patas monkeys, but was inactive as an enzyme inducer and was a nonpromoter in the hamster. [ABSTRACT FROM PUBLISHER]

The dose-response relationships for hepatic cytochrome P450 (CYP) induction by 1,4-bis(2-\[3,5-dichloropyridyloxy])benzene (TCPOBOP) were examined in the male B6C3F1 mouse. TCPOBOP, administered for 14 days at 0.393-96.2 ppm in the diet, caused concentration-dependent induction of hepatic CYP subfamily 2B (CYP2B) protein and of benzyloxyresorufin O -dealkylation. The ED50 values for CYP2B induction, calculated on the basis of immunoreactive CYP2B protein and benzyloxyresorufin O -dealkylation, were 1.2 ppm and 2.2 ppm dietary TCPOBOP, respectively. The maximal catalytic activities observed were 74-95-fold higher than control values. These induction levels were 2.3-2.6-fold greater than those resulting from exposure of the mice to 500 ppm dietary phenobarbital (a prototypic CYP2B inducer). The EC50 values of TCPOBOP for hepatic CYP2B induction were <0.3 mumol/l (serum) and <3.3 mumol/kg (liver). Increases in immunoreactive CYP subfamily 1A and subfamily 3A proteins were also detected, although the maximal induction levels for these subfamilies were relatively low (

Retinoids are proposed chemopreventive agents that inhibit cell proliferation and induce differentiation. Their ability to prevent azoxymethane (AOM)-induced aberrant crypt foci (ACF) and tumors and to modulate cell proliferation was investigated in the colon of male F344 rats. Thirteen retinoids were evaluated for prevention of ACF and two of them, 9-cis-retinoic acid (RA) and 4-(hydroxyphenyl)retinamide (4-HPR), were also evaluated for prevention of colon cancer. The retinoids were administered continuously in the diet starting 1 week prior to the first of two weekly 15 mg/kg i.p. injections of AOM and for a total of either 5 or 36 weeks in order to evaluate their effect on colonic ACF and tumors. At a concentration of 1 mmol/kg diet, 2-(carboxyphenyl)retinamide caused the greatest reduction (57.7%) in the yield of ACF. 9-cis-RA was toxic at 1 mmol/kg so that it was evaluated at 0.1 mmol/kg, resulting in a 41.6% reduction in ACF. The ability of the retinoids to reduce the proliferating cell nuclear antigen (PCNA) labeling index in ACF and in non-involved crypts correlated with their ability to prevent ACF. Both 9-cis-RA (0.1 and 0.2 mmol/kg diet) and 4-HPR (1 and 2 mmol/kg diet) were highly effective in decreasing the yield of AOM-induced colon tumors. In summary, retinoids were demonstrated to reduce cell proliferation and to prevent ACF and tumors in the colon, suggesting promise as preventive agents for colon cancer. [ABSTRACT FROM PUBLISHER]