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Biomedical subjects

M A Friedman

Publications and source records attributed to M A Friedman.

At least 181 records · Page 10Linked to original sources
PubMed1977

In vivo effects of cannabinoids on macromolecular biosynthesis in Lewis lung carcinomas.

Cannabinoids represent a novel class of drugs active in increasing the life span mice carrying Lewis lung tumors and decreasing primary tumor size. In the present studies, the effects of delta9-THC, delta8-THC, and cannabidiol on tumor macromolecular biosynthesis were studied. These drugs inhibit thymidine-3H incorporation into DNA acutely, but did not inhibit leucine uptake into tumor protein. At 24 h after treatment, cannabinoids did not inhibit thymidine-3H incorporation into DNA, leucine-3H uptake into protein or cytidine-3H into RNA.

Animals↗
PubMed1977

Effects of piperonyl butoxide on hydroxylation of 2-acetylaminofluorene in hamster liver.

Single i.p. injection of piperonyl butoxide induces a dose dependent and prolonged inhibition of hamster liver acetylaminofluorene hydroxylation. However, this slight inhibition is the result of a 61% inhibition of acetylaminofluorene-7-hydroxylase activity and a 10 fold stimulation of acetylaminofluorene N-hydroxylase activity. This was confirmed by in vivo experiments. The DNA and RNA binding of acetylaminofluorene-C14 increased 2.1 and 2.4 fold, respectively, 16 hrs after treatment with acetylaminofluorene-C14 in combination with piperonyl butoxide.

2-Acetylaminofluorene↗
PubMed1977

Effects of cannabinoids on L1210 murine leukemia. 1. Inhibition of DNA synthesis.

The effect of cannabinoid derivatives on thymidine-3H uptake in L1210 murine leukemia was determined. In experiments at 200 mg/kg 3 hrs after treatment, the order of activity was delta9-tetrahydrocannabinol less than cannabinol less than cannabidiol less than abnormal cannabidiol less than 11-hydroxy-delta9-tetrahydrocannabinol less than delta8-tetrahydrocannabinol. The inhibitory effect of delta8-tetrahydrocannabinol was 99%. When animals were dosed on consecutive days with delta9-tetrahydrocannabinol and killed on the third day, thymidine-3H incorporation was increased while delta8-tetrahydrocannabinol retained its inhibitory activity under the same conditions. Delta-9-tetrahydrocannabinol and delta8-tetrahydrocannabinol inhibited RNA and protein synthesis in a fashion analagous to the inhibition of DNA synthesis.

Animals↗
PubMed1976

Acute toxicity of dimethylnitrosamine in the presence of inhibitors of DMN demethylase.

The LD50 of DMN was determined in groups of mice in the presence of inhibitors of DMN demethylase. Piperonyl butoxide, dibutylnitrosamine and nitrososarcosine had no effect on the acute toxicity of DMN. Diethylnitrosamine and DMN were markedly synergistic. All mice treated with 100 mg/kg diethylnitrosamine and 10.7 mg/kg DMN died. These results suggest that DMN demethylase may not be involved in the acute toxicity of DMN.

Animals↗
PubMed1976

Inhibition of mouse testicular DNA synthesis by mutagens and carcinogens as a potential sample mammalian assay for mutagenesis.

Since mutagenic substances induce structural changes in DNA, studies were undertaken to determine whether substances would modify DNA replicative activity. DNA synthesis was quantitated 3.5 h after drug administration as uptake into DNA of a 30-min pulse of 10 muCi of [3H] thymidine. Combinations of methylurea (20000 mg/kg) and sodium nitrite (150 mg/kg) administered p.o. resulted in gastric synthesis of nitrosomethylurea and inhibited testicular DNA synthesis by 83%. Combinations of methylurea and sodium nitrite of 1000 and 100 mg/kg respectively inhibited DNA synthesis by 75%. With dimethylamine and sodium nitrite, a combination which results in gastric synthesis of dimethylnitrosamine, inhibitions of 65 and 57% were observed at 2000 mg/kg together with 150 mg/kg and 1000 mg/kg in combination with 100 mg/kg, respectively. In separate experiments, dimethylnitrosamine (50 mg/kg, p.o.) and diethylnitrosamine (100 mg/kg, i.p.) inhibited thymidine uptake by 30 and 89%, respectively. The mutagenic polynucelar hydrocarbon 3-methylcholanthrene (15 mg/kg) inhibited DNA synthesis by 95% and safrole (640 mg/kg), a mutagenic methylenedioxybenzene derivative, inhibited by 60%. Cadmium chloride (10 mg/kg), acetylaminofluorene (160 mg/kg) and dibutylnitrosamine (500 mg/kg) also induced statistically significant effects. Noncarcinogenic analogues of these substances (anthracene, 125 mg/kg; diphenyl-nitrosamine, 500 mg/kg; piperonyl butoxide, 640 mg/kg, and methylurea, 2000 mg/kg in combination with sodium nitrate) were inactive. Highly toxic substances (potassium cyanide, 2.5 mg/kg; 2,4-dinitrophenol, 20 mg/kg; and lead acetate, 150 mg/kg) were also inactive. This index of mutagenicity appears to have considerable sensitivity and therefore may have potential in drug evaluation.

Animals↗
PubMed1976

Suppression of dimethylnitrosamine mutagenicity by nitrososarcosine and other nitrosamines.

Nitrososarcosine, not mutagenic itself in the host-mediated assay using Salmonella typhimurium G46 as indicator organism, lowered the mutant frequency produced by dimethylnitrosamine (DMN). Mutant frequency was significantly depressed when 1.0 g/kg nitrososarcosine was administered by gavage 0.5--2.0 h prior to intramuscular injection of 500 mg/kg DMN. Doses of nitrososarcosine as low as 37.2 mg/kg administered 45 min prior to dimethylnitrosamine treatment produced statistically significant reduction of mutant frequency. Dimethylnitrosamine, diethylnitrosamine and dibutylnitrosamine (500 mg/kg) also partially suppressed the mutant frequency produced by 500 mg/kg DMN when administered 45 min prior to dmn. diethylnitrosamine and dibutylnitrosamine were not found to be mutagenic in this test system.

Animals↗
PubMed1976

Effects of piperonyl butoxide on dimethylnitrosamine metabolism and toxicity in Swiss mice.

The effects of piperonyl butoxide (PB) on the metabolism and toxicity of dimethylnitrosamine (DMN) in Swiss mice were determined. PB, at doses of 10 and 20 mg/kg, inhibited DMN demethylase 45 min after treatment by 18 and 37%. These inhibitory effects were marked 0.5 hr after PB (640 mg/kg) treatment and reached maximal effects at 2 hr when there was 55% inhibition of enzyme activity. The inhibition by PB continued for 24 hr where enzyme activity was suppressed by 35%. At 48 hr after treatment there was stimulation of enzyme activity. Enzyme kinetic determinations showed no change in Km but Vmax decreased from 129 to 49 mumol CH2O/min-g liver. PB (640 mg/kg) inhibited DMN (500 mg/kg; im) mutagenicity in the host-mediated assay, decreasing the mutant frequency by 42%. Paradoxically, PB (640 mg/kg) had no effect on the alkylation of nucleic acids or proteins in mouse liver, kidney, lung, or spleen. In addition, pretreatment with PB (640 mg/kg) had no effect on the LD50 of DMN.

Alkylation↗
PubMed1976

Acute effects of ethionine stereoisomers on hepatic RNA and protein synthesis in swiss mice.

The acute biochemical effects of ethionine have been well studied in rats but not in mice. These results show that both hepatic RNA and protein synthesis in Swiss mice were inhibited by DL-ethionine. Protein synthesis was inhibited 30 to 40 percent 3 hr after 2500 mg/kg DL-ethionine while RNA synthesis was inhibited 80 to 90 percent 3 hr after 625 mg/kg DL-ethionine. Thus ethionine was a far more potent inhibitor of RNA synthesis than of protein synthesis. There was no sex difference in either of these responses. While both stereoisomers were active, the L isomer was a more potent inhibitor of RNA synthesis than was the D isomer. In male mice, 3 hr after 20 mg/kg L-ethionine, RNA synthesis was inhibited 80%, while after D-ethionine it was inhibited only 51%.

Animals↗
PubMed1976

Inhibition of arylhydrocarbon hydroxylase induction in BALB/C mouse liver by delta9-tetrahydrocannabinol.

The effects of single administration of delta9-THC on the induction of arylhydrocarbon hydroxylase activity by phenobarbital and 3-methyl cholanthrene were determined. delta9-THC completely suppressed the induction by phenobarbital and reduced the 3-methylcholanthrene induction from 455% to 177% of control. delta9-THC had no effect on phenobarbital induction when both drugs were administered daily for 2 days and mice killed on the third day. Arylhydrocarbon hydroxylase was not the only enzyme effected as delta9-THC also inhibited the induction of aminopyrine demethylase by phenobarbital. These drugs do not have any interactive effect on microsomal protein synthesis but are potent antagonists in the synthesis of nuclear RNA.

Aminopyrine N-Demethylase↗
PubMed1975

Interactive mutagenicity of sodium nitrite, dimethylamine, methylurea and ethylurea.

Groups of mice were treated per os with sodium nitrite either alone or in combination with nitrosatable amino compounds and tested in the host mediated assay. When mice were treated with sodium nitrite in combination with dimethylamine a small(4-fold) but significant increase in mutant frequency (MF) was observed. Ethylurea or methylurea in combination with sodium nitrite induced 10- or 850-fold increases in MF, respectively. The response to methylurea was dose-dependent with a 6- and 30-fold increase in MF at 5.4 and 11.5 mg/kg NaNO2 and a 6-fold increase at 108 mg/kg methylurea. That this response reflected gastric nitrosation was shown by the disappearance of the response if NaNO2 administration preceded methylurea treatment by 10 min. High MF's were observed if NaNO2 was administered 10 or 20 min after methylurea.

Animals↗
PubMed1975

Parathyroid function in infants of diabetic mothers.

Serum parathyroid hormone and total and ionized Ca, Mg, and P levels were determined serially from birth to 96 hr of age in 28 infants of diabetic mothers (IDM, 15 Class A, 13 Class B, C, D) and their respective mothers at the time of delivery. In spite of marked decreases in concentrations of serum total and ionized Ca from birth to 24 to 48 hr, there was an insignificant increase in serum PTH values over this period in infants of insulin-dependent mothers. Infants of Class A diabetic mothers had an equivocal PTH response. Nineteen term control infants were similarly examined and had a significant increase in serum PTH postnatally. Relatively higher values of serum ionized Ca at birth in IDM were followed by greater decreases in ionized Ca from birth to 24-48 hr of age, and by decreased neonatal parathyroid function. The data support functional hypoparathyroidism as a basis for the hypocalcemia and hyperphosphatemia of IDM. It is speculated that increased concentrations of serum ionized Ca in utero and suppression of activity in the fetal parathyroid glands may be a cause for the functional hypoparathyroidism.

Blood↗
PubMed1975

Antineoplastic activity of cannabinoids.

Lewis lung adenocarcinoma growth was retarded by the oral administration of delta9-tetrahydrocannabinol (delta9-THC), delta8-tetrahydrocannabinol (delta8-THC), and cannabinol (CBN), but not cannabidiol (CBD). Animals treated for 10 consecutive days with delta9-THC, beginning the day after tumor implantation, demonstrated a dose-dependent action of retarded tumor growth. Mice treated for 20 consecutive days with delta8-THC and CBN had reduced primary tumor size. CBD showed no inhibitory effect on tumor growth at 14, 21, or 28 days. Delta9-THC, delta8-THC, and CBN increased the mean survival time (36% at 100 mg/kg, 25% at 200 mg/kg, and 27% at 50 mg/kg, respectively), whereas CBD did not. Delta9-THC administered orally daily until death in doses of 50, 100, or 200 mg/kg did not increase the life-spans of (C57BL/6 times DBA/2)F1 (BDF1) mice hosting the L1210 murine leukemia. However, delta9-THC administered daily for 10 days significantly inhibited Friend leukemia virus-induced splenomegaly by 71% at 200 mg/kg as compared to 90.2% for actinomycin D. Experiments with bone marrow and isolated Lewis lung cells incubated in vitro with delta9-THC and delta8-THC showed a dose-dependent (10(-4)-10(-7)) inhibition (80-20%, respectively) of tritiated thymidine and 14C-uridine uptake into these cells. CBD was active only in high concentrations (10(-4)).

Administration, Oral↗
PubMed1975

Inhibition of epidermal DNA synthesis by cycloheximide and other inhibitors of protein synthesis.

Cycloheximide, pactamycin and tenuazonic acid inhibit protein synthesis in eukaryotic cells. It is the purpose of these studies to determine whether these agents would be effective in vivo inhibitors of epidermal DNA synthesis. Single I.P. administration of 1.5 mg/kg cycloheximide, 0, 1 or 3 hours prior to a 45 minute pulse of thymidine-3H inhibited epidermal DNA synthesis by 68%, 63% and 88%, respectively. This response was dose related at 3.75 hours after cycloheximide with no effect at 0.375 mg/kg and maximal inhibition at 1.5 mg/kg. Epidermal DNA synthesis was inhibited 18, 29 and 62% at doses of 1.5, 3.0 and 6.0 mg/kg pactamycin administered 3 hours before thymidine-3H. Similarly, at doses of 70 and 140 mg/kg tenuazonic acid, epidermal DNA synthesis was inhibited by 50% and 60%, respectively. These data suggest the possible use of protein synthesis inhibitors in epidermal disorders.

Animals↗