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Male Sprague-Dawley rats, 25 days of age, were placed on a control ration and diets containing trypsin (2429 u/g) and tamoxifen (initial level: 4 PPM) at which time, 1,2-dimethylhydrazine was injected s.c. at 20 mg base/kg and continued once/week for 20 weeks. Most of the animals were killed 65 days after injection 20. In view of weight losses, the tamoxifen supplement was decreased to a final level of 0.50 PPM without intervening control diet feeding. The total number of colon adenocarcinomas and the distribution in the proximal and distal portions did not differ significantly from the respective controls and the tumor frequencies in the small intestine were not remarkable. However, the general animal conditions, weight changes and the presence of other tumor types were more extreme as compared to a similar trypsin supplement reported for rats administered carcinogen by gavage once weekly for 15 consecutive weeks. With the latter series, colon adenocarcinoma frequencies were markedly decreased.

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Adult rats with two-thirds of the liver removed were administered diets supplemented with benzodiazepine drugs over a period of 10 days and the mass of organ regenerated or the liver increment ascertained. For a number of the drugs, liver regeneration was stimulated; the effect was more consistent and reproducible in the adult female. On the basis of the lower sensitivity of the male, such animals provided an approach toward rating the hepatotrophic efficacy of the agents and in relation to structure. According to the current classification, hepatotrophic activity was higher with lorazepam, loprazolam, oxazepam and chlordiazepoxide; intermediate with nitrazepam, temazepam, quazepam, halazepam and triazepam and lower with diazepam, clorazepate dipotassium, clobazam and alprazolam. More reproducible responses in terms of g wet and dry liver per 100 g body weight were obtained with sham-operated or intact males. The antagonist, flumazenil, fed at 0.080% was not effective as such nor modified the responses in admixture with several drugs in partially hepatectomized or intact males. In vivo hepatic microsomal changes in protein, cytochrome P-450 or the enzymes, aminopyrine demethylase and benzo[a]pyrene hydroxylase with the various series were not remarkable or sporadic. Among other factors, the liver incremental changes noted currently are dependent on the metabolic intermediate benzodiazepines of varying elimination half-lives which may be distinct from that of the parent drug coupled with the alterations induced by partial ablation of the organ in rats of either sex.

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Sprague-Dawley male rats, 24 days of age, were placed on diets based on a balanced ration as such and supplemented with Brazilian A rabica green coffee bean oil (0.10%), silymarin flavonolignans (0.10%), porcine trypsin (2429 mu/g ration) and ferrous sulfate (0.24% Fe) for a period of 32 weeks. A portion of the controls was switched to the iron salt diet at day 37 when 1,2-dimethylhydrazine was administered by gavage at a dosage of 20 mg/kg (base) and continued weekly for a total of 15 weeks. The colon and small intestinal adenocarcinoma numbers were determined for each group of rats surviving the carcinogen treatment and compared with the respective controls by a statistical design based on Poisson distribution. The results indicate that the adenocarcinoma frequencies of the colon, both total and occurrence in the proximal and distal portions were significantly decreased in the groups fed coffee oil, silymarin group and trypsin. The colon tumor numbers for the iron salt-fed were in the control range except for a decrement in the distal colon for rats on the diet from the start. Small intestinal adenocarcinoma scores with all supplemented diets did not differ significantly from the controls.

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Iron salts supplemented in a basal ratio, were fed to young Sprague-Dawley male rats for prolonged periods and the frequency of colonic adenocarcinomas induced by repeated s.c. injection of 1,2-dimethylhydrazine (DMH) at unit base doses of 9.0 mg/kg, ascertained and compared with the respective controls. In a series employing ferric ammonium citrate (0.46% Fe), in addition to ferrous sulfate (0.11% Fe) and ferric ammonium sulfate (0.12% Fe), DMH injection was started on day 15 and the animals necropsied 22 weeks after the last of 23 doses. The general condition was more involved with the 0.46% Fe diet and the total colonic lesion numbers were in the control range. However, the ferric ammonium sulfate-fed group showed a significant increase in tumors in the distal colon portion. In the second experiment, 15% guar gum as such and in admixture with ferric ammonium sulfate (0.12%) were compared with the respective controls, the first of 20 weekly dosages of DMH being administered on day 28 of the feeding. At 32 weeks following injection 1, the overall lesion differences were not remarkable, but the guar gum ratios engendered decreases in the distal colon tumor frequencies. In general, lesion incidence was extensive, involving 80-100% of the animals per group of the 2 series. Adenocarcinomas occurred in the small intestine and were more prominent in the control and 15% guar gum dietary groups but fewer with the ferric ammonium sulfate supplement.

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Groups of male Sprague-Dawley rats at 39 days of age, were injected s.c. with estradiol benzoate (15 micrograms/kg), cortisone acetate (2.5 mg/kg) and deoxycorticosterone acetate (10.0 mg/kg) in peanut oil, the controls receiving the oil vehicle on days 1 and 3 and weekly thereafter for a total of 32 injections. 1,2-Dimethylhydrazine was administered s.c. weekly after the 1st 2 drug doses, the dosage as base being 9.0 mg/kg for the 1st 7 injections, then 19.4 mg/kg for the last 13 dosages. The rats were killed 31 weeks after the 1st DMH injection. The changes in animal condition at necropsy were moderate to extreme in half of the rats and all survived the 20 DMH injection-schedule; mortality was low per group but elevated with the deoxycorticosterone acetate treatment (40%). Essentially all rats displayed colon adenocarcinomas and the total frequency and the number in the proximal and distal portions were in the control ranges except for the statistically significant decrements in overall and distal colon numbers for the estrogen-treated group and possibly, near-significance in case of the cortisone acetate-injected rats. Small intestinal adenocarcinomas which were more prevalent in the upper areas occurred among the groups. As based on the current findings with estrogen, the trend was in the direction of an inhibiting effect on DMH tumorigenesis in contrast to a stimulatory response reported for androgenized males.

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To evaluate possible nephroblastoma induction in young Sprague-Dawley male rats by 1,2-dimethylhydrazine (DMH), agents including inhibitors and stimulators of the carcinogenesis were tested concurrently in 2 experiments. In series A, rats, 27 days of age, were fed the following as supplements in a basal diet at the final wt% given: hydralazine (0.035%), disulfiram (250 ppm), ferrous sulfate heptahydrate (0.55%; 0.11 g% Fe), isotretinoin (240 ppm), dehydroepiandrosterone (0.30%) in addition to selenium (2 ppm; drinker). At day 15, DMH was injected s.c. at 108 mg base/kg; duration on the diets: 51 weeks. Series B comprised 33 day-old males which were partially hepatectomized (control and indomethacin at 10 mg/l by drinker) or bilaterally gonadectomized for comparison vs sham-operated, and intact groups on s.c. injection of estradiol benzoate (15 micrograms/kg), progesterone (30 mg/kg) and diallyl sulfide (100 mg/kg), the respective controls receiving the peanut oil vehicle. Treatments were begun 8 days post-operative and 17 days later, the single dosage of DMH as in the above was injected. The oil solutions were administered at the specified weekly levels for a total of 52 injections, 2 doses being introduced per week for the 1st 3 weeks. Colon adenocarcinomas comprised the main tumors and occurred in about 15-50% of the rats with total frequencies in the respective control ranges except for decrements with the disulfiram- and iron-fed groups. Renal changes were more involved with series B and nephroblastomas of the left kidney occurred in one animal each of the estradiol benzoate- and diallyl sulfide-injected groups. Of interest, bilateral nephroblastomas were present in one of the saline-injected controls which was gonadectomized. Under the conditions explored, concurrent treatment with DMH inhibitors or synergists had a minimal effect on nephroblastoma induction.

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Young adult Sprague-Dawley rats were partially hepatectomized (two-thirds organ removal) and administered a basal diet supplemented with various animal- and plant-derived enzymes (trypsin, alpha-chymotrypsin, pepsin, lipase, alpha-amylase, malt diastase, ficin and bromelain) over a post-operative period of up to 10 days. Porcine or bovine dialyzed and lyophilized crystalline trypsin products containing 2400-3200 NF u/mg in addition to enteric-coated tablets with trypsin to chymotrypsin in a ratio of 6:1, were tested at supplementary levels of up to 4980 u/g ration. With the weight of tissue regenerated or the liver increment as indicator, trypsin in excess of 1000-1200 u/g ration proved inhibitory. This effect did not extend to alpha-chymotrypsin (levels of up to 4000 u/g diet) and the remaining 6 enzyme products specified above, nor to the s.c. injection of trypsin daily at 12,860 u/rat for the 1st 7 days. The last route promoted little change in increment with soy bean trypsin inhibitor (8.0 mg/rat daily for days 1 to 9). When a portion of the group fed a trypsin supplement of 2000 u/g was injected with phenobarbital i.p. at 80 mg/kg daily on each of the last 3 days, the resulting liver increment rose to the control range. As with lysine and arginine, acids of pertinence in tryptic proteolysis, no significant change was elicited by feeding a diet supplemented with peptone from tryptic digestion of casein. The enzyme-containing diets fed to sham-operated rats over a similar interval, did not affect the wet- or dry-liver weight per 100 g body weight. Microsomal parameters as total protein, cytochrome P-450 and the enzymes, aminopyrine demethylase and benzo[a]pyrene hydroxylase of livers from the partially hepatectomized or sham-operated rats fed trypsin and the other enzyme diets, presented no significant changes in the respective levels. The possible action of dietary trypsin in conjunction with inhibitors and growth factors controlling liver regeneration is discussed.

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In order to evaluate possible carcinogenesis, young adult male Sprague-Dawley rats were fed diets of hydralazine, phenelzine, and isoniazid at levels of 0.020-0.035% for 87 weeks. Hydralazine and isoniazid were also tested by the subcutaneous (sc) route at weekly dosages of 17 and 83 mg/kg, respectively, in both intact and partially hepatectomized rats, but many succumbed after 7 to 49 weeks of treatment. Gastrointestinal lesions were absent and, of the miscellaneous changes, sc lesions occurred sporadically among the control and drug-treated groups. As a further criterion, male weanlings were placed on the diets and, starting on day 15, 1,2-dimethylhydrazine (DMH) was injected sc at 9.0 mg/kg once weekly for the first 7 weeks and twice per week for a total of 23 treatments. The rats were killed 22 weeks after the last injection, at which time colon adenocarcinomas were observed in over 80% per group, the total number being significantly greater for the isoniazid group due to heightened tumor occurrence at the distal colon. The tumor number in the descending colon for phenelzine was also increased but the overall score, as with the hydralazine group, was in the range of the DMH injected controls. Small intestinal adenocarcinomas were lower in number and involved fewer rats on the hydralazine and phenelzine diets as compared to the isoniazid and control groups. Based on the current data, it is concluded that on long term exposure of DMH treated rats to the monoamine oxidase inhibitors, hydralazine and phenelzine are not cocarcinogenic, whereas isoniazid enhances colon carcinogenicity.(ABSTRACT TRUNCATED AT 250 WORDS)

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This study is among the first employing anatomical partial hepatectomy and exposure of the remnant organ to lasers before closure for comparison of biological changes with those of exposed sham-operated groups and the respective controls. Adult male rats were partially hepatectomized leading to removal of two-thirds of the organ and the lateral lobe exposed to Argon (514 nm, 270 mW-3.0 W for up to 120 s; tunable dye, 630 nm, 200 and 500 mW for up to 240 s) and Nd:YAG (1064 nm; 3-8 W, 60-180 s) lasers. Sham-operated rats were treated similarly and with several, 1 or 2 additional sites in the quadrate lobes were irradiated. Possibly, liver damage and penetrability were somewhat greater for the intact rats treated with the Nd:YAG laser and which also displayed liver profile changes over the controls in contrast to the partially hepatectomized. In general, the extent of liver regeneration over a period of 10 days post-operative was not affected by the laser treatment. The mixed function oxidase system reflected small decrements in aminopyrine demethylase and in benzo[a]pyrene hydroxylase for adjacent lesion-free microsomes from the partially hepatectomized and intact groups exposed to Nd:YAD laser (5.0 W, 120 s), respectively.

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Young male Sprague-Dawley rats in 3 groups were fed a basal diet supplemented with 0.10 wt. % each of thalidomide and its imide-analog of much higher teratogenicity, EM 12. Following an induction period of 17 days on the diets, all animals were injected subcutaneously with 1,2-dimethylhydrazine at 20 mg/kg for a total of 20 weekly doses and killed on week 18 after the 20th injection. The total number of colon adenocarcinomas and their occurrence in the proximal and distal portions for the thalidomide-treated rats were similar to those of the respective controls. However, the EM 12-fed group elicited statistically significant increases both in the total and ascending colon-based adenocarcinomas as compared with the control findings, in keeping with its greater teratogenicity and embryotoxicity. The numbers of small intestinal adenocarcinomas were equally higher in the imide-fed groups in contrast to the control frequency.

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Adult rats of either sex and mature females ovariectomized 44 days earlier, were partially hepatectomized under ether anesthesia, leading to two-thirds organ removal. The respective controls were incised and the livers manipulated by hand. At specified p.o. periods, hepatic microsomal total protein, cytochrome P-450 and activities of the enzymes, aminopyrine demethylase and benzo[a]pyrene hydroxylase were determined for the respective pairs and submitted to analysis of variance. The data are expressed as ratios of the sham-operated to the partially hepatectomized group mean values on a percentage basis. For one male series, cytochrome P-450 and the 2 enzyme activities were significantly elevated with the intact rats at 72 and 96 h and 10 days and in yet another series of the same sex, the findings were similar except that only the cytochrome level of the controls was increased at day 10; the ratios normalized by day 21. As screened in a few groups, the changes in microsomal NADPH cytochrome c reductase were not noteworthy. Possible latency periods were shorter for the female series and the hydroxylase activity was elevated in the intact liver microsomes over test periods of 24 h to 10 days. In general, although a trend of increased parameter value for the intact group was apparent and in agreement with several published reports, statistical significance could not be substantiated in many instances, wide variations and sporadic data being encountered. None of the intact group changes in the constants were significant with the ovariectomized series. The effect of an inducer, phenobarbital, was determined in relation to the 10 day-ratios derived for males fed a casein based control diet as such and supplemented with 30 wt % each of glucose, fructose, galactose, maltose and lactose, the last one being screened only in partially hepatectomized rats. Phenobarbital was injected i.p. daily at 80 mg/kg on the last 3 days. Among other changes noted with the respective ratios, each of the intact groups displayed remarkable elevations in the total protein content. Additional comparisons are also advanced for the individual group parameter findings in relation to the control diet- and the 30% glucose-fed animals.

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Groups of mature female Syrian golden hamsters were injected s.c. with peanut oil solutions of estradiol benzoate and progesterone at daily dosages of 10 micrograms and 20 mg, respectively, the controls receiving the vehicle. The male series comprised controls and estrogen-treated. A portion of each group was injected i.p. with phenobarbital at 80 mg/kg daily for the last 3 days and all animals were sacrificed on day 10. Hepatic microsomal total protein, cytochrome P-450 and enzymes, aminopyrine demethylase and benzo[a]pyrene hydroxylase of the steroid-injected groups revealed no definite changes over the controls except for an increase in the hydroxylase activity with the progesterone group. In general, cytochrome P-450 and the enzyme activities were significantly elevated on comparison of the phenobarbital-injected groups versus the uninduced controls. Inter-group comparisons of the phenobarbital-injected females revealed no remarkable changes over the respective controls, but with the males, the hydroxylase activity of the estrogen-treated group was markedly elevated. In contrast to the rat, the hamsters injected with estrogen at the specified dosage, underwent no significant change in the liver weight percentages. However, liver enlargement occurred with progesterone as such or on phenobarbital treatment in comparison with the corresponding control groups.

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Cataractous lenses from men and women averaging 77.7 years of age were sonicated for intervals of 10 min with 0.85% saline under cooling in a laboratory sonicator, followed by centrifugation. The respective supernatants were analyzed for LDH and the weights of the zonal portions obtained by difference. The initial fraction averaged 60 and 47% in solids and LDH, respectively, with decreasing contents to the final harder core residue. The procedures were also applied to calf lenses. Much shorter sonication periods and stepwise increases in wattage from one fraction to the next were also investigated. The calf lens displayed higher LDH activity/mg at settings of 6-8 W in contrast to the cataracts, the initial fraction containing 80% of the enzyme activity and the solids; the values were far lower at settings of 1-3 W. As compared to the sonicated outer layer fractions, the calf nuclear portions showed small but significant decrements in the isoenzymes, LDH-1 and LDH-2, and increases in LDH-4 and LDH-5, possibly indicative of heightened anaerobiasis.

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In a preliminary study, total fatty acids of lipids removed from hair of subjects of either sex with cystic fibrosis (n = 17; average age 8.3 years) and controls (n = 24; average age 9.1 years) were analyzed by gas chromatography. In contrast to the blood lipids in cystic fibrosis which display various fatty acid changes as a depression in 18:2 and increases in 16:0, 16:1, and 18:1, such profiles did not occur with the hair lipids. With the latter, total fatty acids in cystic fibrosis showed decrements in 18:1 and in the lesser concentrations of 20:1 and members below C14 as compared to the respective control series.

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Chemical parameters comprising urea and creatinine nitrogen, cations (Na+, K+, and Ca2+), chloride, phosphorus, protein, cholesterol and enzymes, aminotransferases, alkaline and prostatic acid phosphatases, gamma-glutamyltransferase, creatine kinase, and lactate dehydrogenase were ascertained for semen from groups A (vasectomized), B (oligospermic), and C (normospermic) men, 19 to 55 years of age. Of the parameters, the vasectomized group underwent definite depressions in potassium ion, alkaline phosphatase, aspartate aminotransferase, gamma-glutamyltransferase, and lactate dehydrogenase as compared with the normospermic group; the last three enzymes and, possibly, the urea-creatinine ratio were decreased for the oligospermic group vs. the normospermic men. In the comparison of groups A and B, only the decrements in alanine aminotransferase and lactate dehydrogenase were statistically significant. In corroboration of past reports, CK-BB comprised the main isoenzyme of semen creatine kinase.

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Rats of either sex as intact or partially hepatectomized (two-thirds liver removal) were injected s.c. daily for 7 days post-operatively with natural and synthetic estrogens, androgens or anabolic steroids, progesterone and adrenal cortical hormones and killed on day 10 at which time the livers were processed for microsomal analyses (protein, cytochrome P-450 and enzymes, aminopyrine demethylase and aromatic hydrocarbon or benzo[a]pyrene hydroxylase). Groups were also induced with phenobarbital injected i.p. on the last 3 days at 80 mg/kg each. With the intact males, hexestrol was the only estrogen which caused liver enlargement and at a daily dosage of 1.0 micrograms per rat as well as a decrease in the hydroxylase level. Estradiol benzoate (15 micrograms/rat daily) depressed cytochrome P-450 and the other steroids screened had little effect on the microsomal parameters except for a rise in demethylase with deoxycorticosterone acetate (1.0 mg). A greater sensitivity to estrogens and the other steroid types was noted with the partially hepatectomized males and in the direction of depressions in the microsomal elements, the respective data being expressed as percentages of the controls. Estrogens were better tolerated by the intact female and in general, liver enlargement was remarkable. Microsomal activity was elevated with estradiol benzoate or little affected by estrogens except for depressions in hydroxylase levels with equilin (15 micrograms) and the high dosages of hexestrol and diethylstilbestrol, the last agent also eliciting an increase in cytochrome P-450. No statistically significant effect on the microsomal parameters was observed with the intact female treated with 17-methyltestosterone and the anabolic steroids but decreases occurred on injection with testosterone propionate and the cortical hormones. As with the operated male, partially hepatectomized females exhibited no hepatotrophic response to estrogens and the microsomal changes were moderate with such agents as with the other steroid types and resembling the findings for intact males. Competitive inhibition was followed by Lineweaver-Burke analyses of aminopyrine demethylase in operated females treated with several of the steroids.

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Male rats with 2/3 of the liver removed were administered various drugs and chemical agents demonstrated to be stimulatory to the regenerating liver, mainly as supplements in a basal diet and injected with estradiol benzoate daily for the first 9 days p.o. (overall: 250-350 micrograms/kg), the animals being sacrificed on day 10. Estrogen inhibited liver regeneration in many of the drug-treated groups, the restored organ increments often falling to the range of the injected controls on the basal ration. The adult female displayed a lower sensitivity or more inconsistent responses to several drugs, and generally, estrogen had a minor effect on the ensuing restored organ increment. As tested with a few agents, the behavior of adults ovariectomized 21 or 35 days prior to partial hepatectomy simulated that of the males. A group of compounds, including thianthrene and phenyl sulfide, among others, was hepatotrophic to rats of either sex and the increments were not altered by intervention of estrogen. The inhibitory action of estradiol benzoate also extended to males fed the hormone as a dietary supplement. Moderate to high levels of progesterone or testosterone propionate administered to females elicited liver increments much greater than those due to the drugs as such. In contrast to the partially hepatectomized series, the intact male displayed liver enlargement with test agents but except for few, the inhibition due to estrogen was lower. The intact female findings with several drugs appeared to be more consistent as compared to the liver increment data.

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Male rats were fed a diet supplemented with 0.12% thianthrene or control chow for a period of 10 days after which they were partially hepatectomized, two-thirds of the organ being removed and continued on the diet or switched to the other for the last 10 days. All animals were sacrificed on day 20 and the extent of liver regeneration determined. Intact males were also employed and the wet- and dry-liver weight percentages compared. The thianthrene diet administered for 20 days or p.o. for 10 days elicited extensive regeneration but the effect did not extend to the group switched to the control ration. With the latter, the portion undergoing regeneration was markedly lower owing to the massive amount of tissue extirpated at surgery. The test agent was very stimulatory to the intact male including the group placed on the control diet for the last 10 days. For animals fed thianthrene for 20 days, liver microsomal cytochrome P-450 and aminopyrine demethylase were elevated significantly in the intact series and the last enzyme, in the operated males; the difference in benzo[a]pyrene hydroxylase was not remarkable in either series.

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The levels of the glycolytic enzymes, phosphohexose isomerase, aldolase and LDH and its isozymes, were ascertained in the aqueous of human stillbirths and premature neonate dead (19-24 weeks gestation) and compared with those of older neonates (28-41 weeks) of low survival due mainly to respiratory failure. The fetal aqueous displayed a much greater LDH-P level (mean mU/ml +/- SEM: 45,600 +/- 2550; 72 eyes) in contrast to the near-term infant value (2420 +/- 615; 27 eyes) and 8-20 times higher aldolase and phosphohexose isomerase levels. LDH-P of the fetal vitreous was much lower (5820 +/- 860 mU/ml; 25 eyes) and for lens employed as a filtered homogenate in saline (1:20), amounted to 52.2 +/- 4.2 mU/mg lens (24 eyes). The distribution of LDH isozymes in the fetal vitreous and lens homogenate and the near-term neonate aqueous as determined by polyacrylamide disc electrophoresis, was similar to that of the fetal aqueous, LDH-1 and LDH-5 being least and LDH-3 and LDH-4, the highest. A few small but significant differences were apparent as compared to the fetal aqueous isozymes and included decrements in vitreous LDH-4, lens LDH-3 and neonatal aqueous LDH-3 and increases in vitreous LDH-2 and near-term aqueous LDH-4. The current findings may have application to retinoblastoma for which higher aqueous LDH levels have been reported and employed as a diagnostic adjunct. However, the fetal aqueous LDH values far exceed those encountered in this embryonal-type tumour.

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