The modifying effect of folinic acid on diphenylhydantoin-induced teratogenicity in mice

To test the alleged association between diphenylhydantoin sodium (DPH) teratogenicity in animals and folic acid antagonism, inseminated female mice were treated ip with 50 mg/kg of DPH, a dose reported to be teratogenic in mice. They were given concurrent im doses of folinic acid (FA) of 1, 10, 20, 30, 40 and 100 mg/kg. The incidence of cleft palate in each group was determined. Statistical evaluation of the data demonstrated marked litter variance and a nonlinear modifying response. The incidence of cleft palate was not significantly different between groups receiving DPH alone and groups receiving DPH plus high doses (40–100 mg/kg) of FA or low doses (20 mg/kg) of FA. However, there was a significant difference (p < 0.05) in the incidence of cleft palate between the groups receiving the high and low doses of FA. The data suggest that the various doses of FA, given concurrently with DPH, offer no significant protection against the development of cleft palate in mice, but do influence its incidence in a nonlinear fashion.     

Liver damage following paraquat in selenium-deficient and diethyl maleate-pretreated mice

Human paraquat poisoning often includes a transient impairment of liver function before death due to pulmonary edema and fibrosis. The purpose of this study was to examine the effect of paraquat on liver function in mice fed normal lab chow, in mice fed a selenium (Se)-deficient diet for 5 weeks, and in diethyl maleate-pretreated mice (1.2 ml/kg). Liver function was determined by evaluating plasma activity of glutamic-pyruvic transaminase (SGPT), hexobarbital sleeping time, and plasma disappearance of indocyanine green (ICG). Paraquat, in doses as high as the LD50 (30 mg/kg, ip) did not alter hexobarbital sleeping time or SGPT activity in lab chow-fed mice. Selenium-deficient, paraquat-treated mice, however, had significantly elevated SGPT activity (31 units in control mice, > 1000 units in treated group), had longer hexobarbital sleeping times (from 30 min to > 180 min), and retained ICG in plasma (15-min plasma ICG concentrations of 8.4 mg/100 ml in Se-deficient paraquat-treated group vs 1.3 mg/100 ml in controls). Liver damage in Se-deficient treated mice was also observed histologically. In mice treated with paraquat, diethyl maleate pretreatment produced similar, but not as marked, effects as Se deficiency. The results suggest that paraquat alone is not hepatotoxic in mice; however, Se deficiency or diethyl maleate pretreatment may shift the organ specific toxicity of paraquat toward the liver.     

Teratogenicity of three polychlorinated dibenzofurans in C57BL/6N mice

Polychlorinated dibenzofurans (PCDFs) are widespread environmental contaminants which have been detected in human tissues and implicated in several poisoning incidents. Their toxic effects are similar to those observed with other related halogenated aromatic hydrocarbons such as TCDD. The teratogenic effects of three PCDFs, 1,2,3,7,8-pentachlorodibenzofuran (1-PeCDF), 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF), and 1,2,3,4,7,8-hexachlorodibenzofuran (HCDF), were assessed in C57BL/6N mice. Pregnant mice were exposed on Gestation Days 10-13 to 10 ml corn oil/kg containing PCDFs. The dams were killed on Gestation Day 18 and maternal and fetal toxicity were assessed. All three compounds were highly teratogenic, with very steep and parallel dose-response curves for the two diagnostic indicators of dioxin-like teratogenicity, hydronephrosis, and cleft palate. 4-PeCDF was the most teratogenic with an ED50 of 36 micrograms/kg for cleft palate and 7 micrograms/kg for hydronephrosis. 4-PeCDF was approximately 4 times as potent as 1-PeCDF and 10 times as potent as HCDF. The teratogenic responses occurred at a dose below that where any obvious maternal or fetal toxicity was detected. Thus, these three compounds cause teratogenic responses similar to those seen with TCDD but are only 1/10 to 1/100 as potent.     

Teratogenic acitivity of the antiepileptic drugs phenobarbital,phenytoin, and primidone in mice

The teratogenic activity of phenobarbital, phenytoin, and primidone was studied in mice derived from the ICI pathogen free strain. The drugs were administered in the diet or by gastric intubation either from days 6–16 or 12–16 of pregnancy (day of vaginal plug is day 1). This covered the period during which the mice are susceptible to agents inducing cleft palate. The mothers were killed 1 day before term and the fetuses were examined. Cleft palates were rarely seen in the controls, the incidence being only 3 out of 1103 (0.3%) fetuses. The incidence of cleft palate in mice treated with phenobarbital 50 or 150 mg/kg in the diet was 0.6 and 3.9%, with phenytoin 40 and 120 mg/kg by intubation, or 250 mg/kg in the diet was 0, 11.1 and 10.2%, and with primidone 100 to 250 mg/kg by intubation or 500–2500 mg/kg in the diet ranged up to 15%. Since changes in blood folate concentrations following the use of anticonvulsants might be related to the teratogenic effects observed, an attempt was made to antagonize the effects by the simultaneous administration of folinic acid. Folinic acid had no teratogenic action of its own, and had no effect on the incidence of cleft palate induced by phenobarbital in the diet, or by phenytoin by gastric intubation. However, it did significantly potentiate the teratogenic effects of phenytoin administered in the diet (p < 0.002) but significantly reduced the teratogenic effect of primidone given in the diet (p < 0.034).     

Dietary fat--a requirement for induction of mixed-function oxidase activities in starved-refed rats

Male rats were starved 0-48 hr, and then refed diets containing 0% (F.F.) to 20% corn oil (C.O.) lab chow or 20% coconut oil (C.C.O.) for 1-4 days. Some received phenobarbital sodium (80 mg/kg, i.p. daily) for 1-3 days prior to decapitation. Five cytochrome P-450-dependent indicators were assayed as measures of altered hepatic microsomal function: ethylmorphine N-demethylase (EMDM), N-nitrosodimethylamine (DMN)-N demethylase, aniline hydroxylase (AH), benzo[a]pyrene hydroxylase (AHH) and CO-difference spectra (P-450). Increasing dietary corn oil (0, 0.5, 10, 20%) in control rats resulted in a progressive increase in the activities of these five enzymes. Dietary fat influenced phenobarbital (Pb) inducibility of all mixed-function oxidase (MFO) enzymes measured except AHH. Pb induced the remaining enzymes only 11-22% in animals fed fat-free diet as compared to 119-246% in animals fed coconut oil and corn oil. Rats fed fat-free diet for 21 days without prior food deprivation and administered Pb had 79% more EMDM, 34% more AH and 120% more P-450 than non-induced controls, whereas rats fed 20% corn oil diet had 227% more EMDM, 143% more AH and 128% more P-450. A requirement of dietary fat for induction of MFO by Pb was demonstrated by these starvation-refeeding experiments. Coupled with data recovered from the 21-day studies, these experiments suggest that a compensatory mechanism may be operative during chronic feeding of the fat-free diet to partially return inducibility to the drug-metabolizing system.     

Synergistic teratogenic effects induced by retinoids in mice by coadministration of a RARalpha- or RARgamma-selective agonist with a RXR-selective agonist

To study the interaction of retinoid-induced limb defects and cleft palate on day 11 of gestation, a RXR-selective agonist (AGN191701, an arylpropenyl-thiophene-carboxylic acid derivative, 20 mg/kg orally) was coadministered with a RARalpha-agonist (Am580, an arylcarboxamidobenzoic acid derivative, 5 mg/kg orally) to NMRI mice. AGN191701 was neither fetotoxic nor teratogenic at the dose used but potentiated Am580-induced limb defects and cleft palate and prevented Am580-induced fetal weight retardation. These results suggest that Am580-induced limb defects and probably cleft palate on day 11 of gestation may be mediated via RARalpha-RXR heterodimerization, particularly in the absence of toxicokinetic interactions. AGN191701 was also coadministered with a RARgamma-agonist (CD437, an adamantyl-hydroxyphenyl naphthoic acid derivative, 15 mg/kg orally) on days 8 and 11 of gestation to investigate which CD437-induced defects are mediated via RARgamma-RXR heterodimerization. On day 8 of gestation, AGN191701 potentiated CD437-induced embryolethality, exencephaly, spina bifida aperta, cleft palate, and tail defects, as well as visceral and skeletal defects, but not micrognathia. On day 11 of gestation, the incidence of CD437-induced cleft palate and limb defects was also potentiated when coadministered with the RXR agonist. These results suggest that synergistic teratogenic effects can be induced by coadministration of two receptor-selective retinoids, indicating the importance of RARalpha-RXR and RARgamma-RXR heterodimers in producing structural defects during organogenesis.     

Effects of chronic ethanol administration in the rat: relative dependency on dietary lipids--III. In vivo tolerance to hexobarbital.

Chronic administration of ethanol with either a high-fat (35% cal., including 2% cal. as linoleate) or a low-fat (2% cal. as linoleate) diet reduces similarly the hexobarbital sleeping times in the rat. Ethanol decreased the plasma and total body half-lives of hexobarbital in both dietary models, but they were decreased significantly more with the high-fat diet. A good correlation between hexobarbital plasma half-life and sleeping time was found only with the high-fat dietary model; the sleeping time was not a good index of hexobarbital metabolism in the low-fat model. Ethanol-fed rats awaken with significantly higher hexobarbital concentrations in brain and other tissues; this phenomenon is significantly more important in the high-fat model. Ethanol, administered chronically in nutritionally adequate liquid diets, increases tolerance to hexobarbital by increasing drug disposition and by decreasing central nervous system sensitivity. Both factors in tolerance are altered by modifications of the dietary lipid intake.     

Inhibition and induction of drug metabolism by psoralens: alterations in duration of sleep induced by hexobarbital and in clearance of caffeine and hexobarbital in mice.

1. Hexobarbital (100 mg/kg i.p.) sleeping times in male CD-1 mice pretreated (-1 h) with a single i.p. injection of 150 mumol/kg of psoralen or coumarin analogues were increased, most markedly (6-fold) by linear, methoxy-substituted psoralens. 2. Hexobarbital sleeping times of mice which received three daily injections (231 mumol/kg; 50 mg/kg) of 8-methoxypsoralen (8-MOP) were 44% of controls (corn oil). 3. The whole-body half-life of caffeine (1 mg) in mice was 10.2, 1.2, and 0.37 h following 8-MOP (50 mg/kg per day) x 1, vehicle, and 8-MOP x 3 respectively. 4. The whole-body concentrations of hexobarbital (100 mg/kg dose) in mice 30 min after dosing were 14.3 +/- 0.9, 8.4 +/- 0.3, and 5.2 +/- 0.5 micrograms/ml (1 mouse = 150 ml) following 8-MOP (50 mg/kg per day) x 1, vehicle, and 8-MOP x 3 respectively. 5. It is concluded that, administered acutely, psoralen analogues inhibit hexobarbital metabolism in mice; and 8-MOP administered acutely inhibits the metabolism of caffeine and hexobarbital, but administered repeatedly increases their metabolism.     

The effects of pentachloronitrobenzene, hexachlorobenzene, and related compounds on fetal development.

Pentachloronitrobenzene (PCNB) containing a number of contaminants produced renal agenesis and cleft palate in $\text{C57B1}\text{6}$ mice, cleft palate in CD-1 mice, but was not teratogenic in CD rats. The major contaminant was hexachlorobenzene (HCB), which produced cleft palates and some kidney malformations in CD-1 mice. Purified PCNB (<20 ppm HCB) showed more maternal toxicity than the contaminated PCNB and resulted in a few cleft palates in the fetuses; there were no kidney malformations with purified PCNB. Thus, the teratogenic activity of contaminated PCNB was probably due to the HCB. Tetrachloronitrobenzene, a contaminant, and pentachloroaniline, a metabolite of PCNB, were not teratogenic in mice or rats. Pentachlorophenol was not teratogenic in rats. Tissue distribution of PCNB, its metabolites pentachloraniline and methyl pentachlorophenyl sulfide, and the contaminants pentachlorobenzene and HCB were studied in pregnant $\text{C57B1}\text{6}$ mice. The tissue distribution of HCB and pentachlorobenzene was studied in pregnant CD-1 mice. Neither PCNB nor pentachlorobenzene accumulated in tissues. This was in contrast to HCB which accumulated in various tissues such as fat, urinary bladder, skin, and thymus.     

Teratogenicity of oral diazepam and diphenylhydantoin in mice

Diazepam (DAP) and diphenylhydantoin (DPH) have anticonvulsant activity and structural similarities. Diphenylhydantoin is teratogenic in the mouse. The effects upon the offspring of mice treated orally with DAP or DPH during pregnancy were studied. DPH, 45, 87.5, or 125 mg/kg, and equimolar doses of DAP, 50, 100, or 140 mg/kg and DAP, 500 mg/kg, were administered orally once daily for 3 days on gestation days 8–10 or days 11–13; or for 1 day only between days 8 and 15 (vaginal plug = day 1). Diazepam, 280 or 400 mg/kg, were administered once only between days 11 and 14. All drugs were suspended in sodium carboxymethylcellulose (CMC 0.5%). The animals were sacrificed on day 19 and the fetuses were weighed and examined. Significant (p ≤0.05) increases of cleft palates over CMC controls were found in offspring following 3-day maternal administration of DAP, 140 mg/kg and DPH, 87.5 or 125 mg/kg on days 11 to 13; and single-day administration of DAP 400 mg/kg on days 11 to 14; and of DAP, 500 mg/kg and DPH, 125 mg/kg on days 11 to 15. There was a greater incidence of significant increases of resorptions and significantly depressed fetal body weights following single-day administration of DAP, 500 mg/kg than after all other treatments. In conclusion, oral DPH and oral DAP, at a higher dosage level, produce a similar teratogenic effect, cleft palate, in the Swiss-Webster mouse.     

Comparative study of the teratogenicity of phenobarbitone,diphenlhydatoin and carbamazepine in mice

Three selected anticonvulsants, phenobarbitone (PHB), diphenylhydantoin (DPH) and carbamazepine (CAA) were examined for embryotoxic and teratogenic activity in albino mice. After oral treatment of the dams during the period of organogenesis (days 6–15 of gestation) with both PHB and DPH in doses causing marked symptoms and signs of toxicity (40 and 170 mg/kg/day respectively), an abnormally high incidence of cleft palate was observed in the foetuses (4.3% and 9.3% resp.). In a cumulative control group of foetuses, the incidence of this particular malformation was only 0.13%. No significant change in the malformation rate was seen after the administration of CAA in doses up to 250 mg/kg/day.Slight to moderate retardation of foetal growth was noted after treatment with DPH and CAA, but onlu at the higher and toxic dose levels. DPH also increased the incidence of early embryonic deaths (deciduomata).     

Induction of hepatic drug-metabolizing enzymes by cyclic fatty acid monomers in the rat

The effects of cyclic monomers on the activities of several drug-metabolizing enzymes were evaluated. Female Wistar rats were fed, for 4 wk, a semi-synthetic diet containing different quantities of cyclic monomers isolated from linseed oil heated at 275 degrees C for 12 hr under nitrogen. Microsomal proteins and cytochrome c were significantly increased in rats fed a diet containing 0.1 or 1% cyclic monomers. Aminopyrine demethylation, a model reaction preferentially induced by phenobarbital, was increased by this treatment. NADPH-cytochrome P-450 reductase was also stimulated. Moreover, ethoxyresorufin deethylation, known to be greatly increased by methylcholanthrene-type inducer was only increased threefold by this treatment. The activity of p-nitrophenol UDP-glucuronosyl transferase decreased while the conjugation of bilirubin was stimulated. These results suggest that cyclic monomers isolated from heated linseed oil show some characteristics of phenobarbital-type inducers.     

Inhibition and induction of drug metabolism by psoralens: Alterations in duration of sleep induced by hexobarbital and in clearance of caffeine and hexobarbital in mice

1. Hexobarbital (100?mg/kg i.p.) sleeping times in male CD-1 mice pretreated (-1?h) with a single i.p. injection of 150 μmol/kg of psoralen or coumarin analogues were increased, most markedly (6-fold) by linear, methoxy-substituted psoralens.

2. Hexobarbital sleeping times of mice which received three daily injections (231 μmol/kg; 50?mg/kg) of 8-methoxypsoralen (8-MOP) were 44% of controls (corn oil).

3. The whole-body half-life of caffeine (1?mg) in mice was 10˙2, 1˙2, and 0˙37?h following 8-MOP (50?mg/kg per day) × 1, vehicle, and 8-MOP × 3 respectively.

4. The whole-body concentrations of hexobarbital (100?mg/kg dose) in mice 30?min after dosing were 14˙3±0˙9, 8˙4±0˙3, and 5˙2±0˙5 μg/ml (1 mcuse = 150 ml) following 8-MOP (50?mg/kg per day) × 1, vehicle, and 8-MOP × 3 respectively.

5. It is concluded that, administered acutely, psoralen analogues inhibit hexobarbital metabolism in mice; and 8-MOP administered acutely inhibits the metabolism of caffeine and hexobarbital, but administered repeatedly increases their metabolism.     

Fatty acid composition of single brain structures following different alpha linolenate dietary supplementations

Weanling female rats randomly divided into three groups were fed a basal alipidic diet added with 10% (w/w) corn oil, soybean oil or linseed oil. After thirty and ninety days of dietary treatment the rats were killed and the fatty acid composition of brain, optic nerve and visual cortex was determined. The results demonstrate a different sensitivity to the diet of the different structures examined and, for the linseed oil treated rats, a strong decrease in the proportions of the total (n-6 + n-3) polyunsaturated fatty acids in all the structures examined.     

Effects of methylmercury on hypnotic action of hexobarbital, liver hydroxylase and cytochrome P-450 in mice

The effects of methylmercury hydroxide (MeHgOH) on the hypnotic action of hexobarbital was investigated in adult 129/SvSl mice of both sexes. It was found that there was no sex difference in the response to MeHgOH treatment. The action of MeHgOH was intimately related to the interval between MeHgOH administration and the test of hexobarbital hypnosis. A biphasic effect was observed. An initial dose-dependent prolongation of hexobarbital hypnosis was observed in animals pretreated with MeHgOH 24 h earlier. If the interval was extended from 24 h to 1 week, a shortening of sleeping time was observed in MeHgOH treated animals. The animals recovered from the effects of MeHgOH in 3 weeks. The initial effect of MeHgOH was found closely related to the decrease in the rate of hexobarbital metabolism in the liver through lowering of cytochrome P-450 concentration. On the other hand, the delayed shortening of hexobarbital hypnosis was not related to the rate of hexobarbital metabolism. It is assumed that the delayed effect of MeHgOH on the hexobarbital hypnosis is due to MeHgOH acting on the central nervous system to decrease its sensitivity to hexobarbital via interaction with the barbiturate receptors on the GABA-chloride ionophore complex. In animals exposed in utero to MeHgOH, it was found that the duration of hexobarbital-induced sleeping time was significantly longer in the offsprings tested for hexobarbital hypnosis 3.5 months after birth following prenatal exposure to MeHgOH. Repeated administration of hexobarbital to adult offsprings prenatally exposed to MeHgOH and to control mice shortened hexobarbital sleeping time, however, the maximum shortening capacity was smaller in the treated group. It is concluded that the hypnotic action of hexobarbital in mice can be altered by MeHgOH exposure both prenatally and postnatally. The effects of prenatal exposure to MeHg were observed in adult offsprings, indicating that MeHg may have a functional teratogenic effect on barbiturate-induced hypnosis in the absence of gross anomalies.     

Hexobarbital sleeping time and drug metabolism in rats with ligated bile ducts—A lack of correlation

Hexobarbital sleeping time is commonly used as an index of the activity of hepatic microsomal drug-metabolizing enzymes in animals. This report describes anomalies between hexobarbital sleeping time and the rate of metabolism in vitro by microsomal enzymes in rats after bile duct ligation (BDL). The duration of hexobarbital sleeping time, 2–24 hr after BDL, was approximately twice that of sham-operated controls. No significant decrease in the activity of microsomal aminopyrine demethylase, aniline hydroxylase, hexobarbital oxidase or the amount of cytochrome P-450 was detected during this period. A further prolongation of hexobarbital sleeping time was observed 48–72 hr after BDL, and this was accompanied by a significant impairment of drug metabolism in vitro. The effect of BDL on hexobarbital sleeping time was independent of the route of administration. Thiopental sleeping time was prolonged at 12 and 72 hr after BDL. Zoxazolamine paralysis time was prolonged at 72 hr after BDL, but not at 12 hr. Plasma protein binding of hexobarbital and thiopental was not altered by hyperbilirubinemia. These data suggest that changes in drug metabolism are not responsible for the prolongation of hexobarbital sleeping time during the early phase of cholestasis caused by BDL.     

Retinoic acid and 2,3,7,8-tetrachlorodibenzo-p-dioxin selectively enhance teratogenesis in C57BL/6N mice

TCDD is one of the most toxic man-made compounds and an extremely potent teratogen in mice. Many of its toxic symptoms resemble those seen during vitamin A deficiency. Vitamin A and its derivatives, such as alltrans-retinoic acid (RA), are also teratogenic in mice, as well as many other species. Both TCDD and RA produce cleft palate in susceptible strains of mice. However, while TCDD produces hydronephrosis, RA does not, and TCDD does not produce limb bud defects while RA does. To determine whether TCDD and RA would enhance or antagonize the teratogenic effects of the other compound, C57BL/6N dams were treated po on Gestation Day (gd) 10 or 12 with 10 ml corn oil/kg containing TCDD (0-18 micrograms/kg), RA (0-200 mg/kg), or combinations of the two chemicals. Dams were killed on gd 18 and toxicity and teratogenicity assessed. Coadministration of TCDD and RA had no effect on maternal or fetal toxicity beyond what would be expected by either compound alone. Cleft palate was induced by RA at lower doses on gd 10 than on gd 12, but by TCDD at lower doses on gd 12 than on gd 10. Sensitivity to TCDD-induced hydronephrosis was similar on both gd 10 and 12. The limb bud defects were only observed when RA was administered on gd 10, not when given on gd 12. No other soft tissue or skeletal malformations were related to administration of TCDD or RA. No effect of TCDD was observed on the incidence or severity of limb bud defects induced by RA, nor did RA influence the incidence or severity of hydronephrosis induced by TCDD. However, the incidence of cleft palate was dramatically enhanced by coadministration of the xenobiotic and vitamin. On both gd 10 and 12, the dose-response curves for cleft palate induction were parallel, suggesting some similarities in mechanism between the two compounds. However, combination treatment resulted in a synergistic response that varied with the stage of development and was tissue specific.     

Inhibition of hepatic drug-metabolizing enzymes by arachidonic acid.

1. The effects of arachidonic acid on hepatic drug-metabolizing enzymes was investigated in male ICR-Swiss mice. 2. A single administration of arachidonic acid, 100 mg/kg i.p., doubled the hexobarbital sleeping time. Arachidonic acid in vitro gave a type I binding spectrum with hepatic microsomes; it inhibited the metabolism of hexobarbital and of ethylmorphine, two type I binding drugs, but not that of aniline, a type II binding drug; the inhibition of hexobarbital metabolism by arachidonic acid was competitive. 3. Repeated administration of arachidonic acid up to a total dose of 1000 mg/kg i.p., either in the course of 5 hours, or in the course of 5 days, decreased microsomal cytochrome P-450 levels and NADPH-cytochrome c reductase activity. 4. It is concluded that the administration of arachidonic acid may impair drug metabolism in two ways, mainly, by competitively inhibiting the activity of drug-metabolizing enzymes, and secondarily, by decreasing the hepatic concentration of these enzymes.     

Effects of dietary lipids on whole-body retention and organ distribution of organic and inorganic mercury in mice.

The effect has been investigated of dietary lipids on the whole-body retention and organ distribution of organic and inorganic mercury in mice. A single oral dose of methylmercury chloride or mercuric chloride labelled with 203Hg was given to female NMRI mice fed semi-synthetic diets containing varying amounts (5, 10, 20 or 50%) of energy derived from lipid (coconut oil, soya oil, or cod liver oil). The whole-body retention and relative organ distribution of mercury depended on diet composition. Thus, a significant reduction of the whole-body retention of mercury was seen in mice fed a diet containing 50% cod liver oil compared with mice fed a diet containing 50% coconut oil. After oral administration of mercuric chloride the relative deposition of mercury in the kidneys increased while that in the liver decreased with increasing concentrations of soya oil or coconut oil in the diet. The whole-body retention of mercury after treatment with methylmercury chloride was significantly decreased in mice fed cod liver oil compared with mice fed coconut oil; there was no difference between mice fed cod liver oil and those fed soya oil. The relative disposition of mercury was significantly higher in all organs of mice fed a diet containing 20% energy from cod liver oil compared with mice fed a diet containing 20% energy from soya oil. The present study demonstrates that diet composition is of major importance to the toxicokinetics of methylmercury and mercuric mercury.     

Effect of various diets on the expression of phase-I drug-metabolizing enzymes in livers of mice

Abstract

1. Previous studies have shown that diets can alter the metabolism of drugs; however, it is difficult to compare the effects of multiple diets on drug metabolism among different experimental settings. Phase-I-related genes play a major role in the biotransformation of pro-drugs and drugs.

2. In the current study, effects of nine diets on the mRNA expression of phase-I drug metabolizing enzymes in livers of mice were simultaneously investigated. Compared to the AIN-93M purified diet (control), 73 of the 132 critical phase-I drug-metabolizing genes were differentially regulated by at least one diet. Diet restriction produced the largest number of changed genes (51), followed by the atherogenic diet (27), high-fat diet (25), standard rodent chow (21), western diet (20), high-fructose diet (5), EFA deficient diet (3) and low n-3 FA diet (1). The mRNAs of the Fmo family changed most, followed by Cyp2b and 4a subfamilies, as well as Por (from 1121- to 21-fold increase of theses mRNAs). There were 59 genes not altered by any of these diets.

3. The present results may improve the interpretation of studies with mice and aid in determining effective and safe doses for individuals with different nutritional diets.