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C C Willhite

Publications and source records attributed to C C Willhite.

At least 55 records · Page 3Linked to original sources
PubMed1986

Structure-activity relationships of retinoids in developmental toxicology. II. Influence of the polyene chain of the vitamin A molecule.

The comparative teratogenic potencies of 7,8-dihydroretinoic acid, 7,8-dehydroretinoic acid, 9,10-dihydroretinoic acid, 9-cis-retinal, hydroxenin, oxenin, the C15 analog of all-trans-retinoic acid, abscissic acid, beta-C14 aldehyde, beta-ionone, and psuedoionone were determined in golden Syrian hamsters and compared with that of all-trans-retinoic acid. A single oral dose of each retinoid on Day 8 of gestation failed to induce signs of retinoid intoxication in the dams and the maternal weight gain was not affected significantly, except after treatment with beta-C14 aldehyde, pseudoionone, and the lowest dose of 9-cis-retinal, where maternal weight was depressed. A significant teratogenic response was observed after intubation of 7,8-dihydroretinoic acid, 7,8-dehydroretinoic acid, or 9-cis-retinal. The highest dose of hydroxenin (equivalent to nearly seven times an equimolar teratogenic dose of all-trans-retinoic acid) showed a limited teratogenic response. None of the remaining retinoids induced terata. The results suggest that the side chain plays an important role in retinoid embryotoxicity and that even minor structural alterations of retinoids at the side chain can abolish teratogenic activity. The present results indicate that a polyene chain of greater than five carbon atoms was necessary for retinoid teratogenic activity and that the presence of the ring, the nine-carbon side chain, and the acidic polar terminus was insufficient to ensure teratogenic activity. Retinoid teratogenicity in hamsters required the hydrophobic ring, a terminal polar group with an acidic pKa, and the hydrophobic, curved plane of the tetraene chain.

Animals↗
PubMed1986

Effect of cyanogenic glycosides and protein content in cassava diets on hamster prenatal development.

Cassava is a staple food for 450-500 million people in 26 tropical countries. Groups of pregnant hamsters were fed diets consisting of cassava meal:laboratory chow (80:20) during Days 3-14 of gestation. One low cyanide (sweet) cassava meal and one high cyanide (bitter) cassava meal were studied. One additional group was fed a diet which resembled cassava in nutritional value, but which lacked the cyanogenic glycosides. Thiocyanate concentrations increased significantly in the urine and blood of dams fed cassava diets. Increased tissue thiocyanate concentrations were observed in fetuses recovered from cassava-fed dams. Cassava-fed dams gained significantly less weight than did control animals and their offspring showed evidence of fetotoxicity. Reduced fetal body weight and reduced ossification of sacrocaudal vertebrae, metatarsals, and sternebrae were associated with cassava diets. High cyanide cassava diets were also associated with a significant increase in the numbers of runts compared to litters from dams fed either low protein or laboratory stock diets.

Animals↗
PubMed1986

Comparative metabolism of linamarin and amygdalin in hamsters.

Rates of cyanide liberation resulting from hydrolysis of the cyanogenic glycosides linamarin, amygdalin and prunasin by a crude beta-glucosidase prepared from hamster caecum were studied in vitro. In addition, hamster blood cyanide and thiocyanate concentrations were determined at 0.5, 1, 2, 3 and 4 hr after an oral dose of 0.44 mmol linamarin or amygdalin/kg body weight. Plots of cyanide liberated v. time for linamarin and prunasin yielded straight lines. A similar plot for amygdalin was curvilinear, with the rate of cyanide release increasing with time. At 10(-3) M substrate concentrations, the average rates of hydrolysis of prunasin, amygdalin and linamarin were 1.39, 0.57 and 0.13 nmol/min/mg protein, respectively. Lineweaver-Burk plots yielded apparent Km and Vmax values of 3.63 X 10(-5) M and 0.35 nmol/min/mg protein, respectively, for amygdalin, and 7.33 X 10(-3) M and 1.04 nmol/min/mg protein, respectively, for linamarin. Blood cyanide concentrations following amygdalin treatment reached their highest level (130 nmol/ml) 1 hr after dosing and remained elevated until 3 hr after treatment. Blood cyanide concentrations following linamarin treatment reached their highest level (116 nmol/ml) after 3 hr and then declined immediately. Area under the blood cyanide concentration-time curve was 395 nmol-hr/ml for amygdalin and 318 nmol-hr/ml for linamarin. The results suggest a faster rate of enzymatic hydrolysis and cyanide absorption for amygdalin than for linamarin.

Amygdalin↗
PubMed1986

Isotretinoin-induced craniofacial malformations in humans and hamsters.

Oral administration of 40-80 mg/d of isotretinoin (13-cis-retinoic acid, Ro 4-3780, Accutane) during the first month of human pregnancy can induce severe congenital malformation. The human Accutane dysmorphic syndrome includes rudimentary external ears, absent or imperforate auditory canals, a triangular microcephalic skull, cleft palate, depressed midface, and anomalies of the brain, jaw, and heart. Children who suffer from this syndrome have large occiputs with narrowing of the frontal bone. Microphthalmia is reported in two cases; notations are made about the orbits in three cases; and the fact that infants could not follow with their eyes is noted in three cases. A decrease in muscle tone is noted in six, cleft palate is present in four, and limb reduction defects are described in two. The cardiac malformations usually include overriding aorta, interrupted or hypoplastic aortic arch, and septation defects of atria and ventricles. There are at least two cases of abnormal origin of the subclavian arteries. Oral isotretinoin in the pregnant hamster also induces similar congenital malformations. A human case of isotretinoin-induced dysmorphia is presented and compared with other affected infants and affected hamsters. The metabolic fate and pharmacokinetic parameters of isotretinoin in humans and rodents are discussed in relation to the teratogenic response. The results suggest that humans are approximately 16 times more sensitive to the teratogenic effects of oral isotretinoin than are hamsters.

Abnormalities, Drug-Induced↗
PubMed1985

Teratogenic profile of retinylidene methyl nitrone and retinol in Swiss-Webster mice.

A single oral dose of 75 mg/kg of all-trans-retinol or all-trans-retinylidene methyl nitrone, retinoids with potential cancer chemopreventive properties, on one of five successive days of embryogenesis resulted in a shift in the pattern of developmental anomalies in fetal mice. Treatment on days 7, 8, or 9 with retinal primarily induced malformations of the head whereas treatment on day 11 induced bilateral forelimb reduction defects. Treatment on day 8 with either retinoid produced the highest in utero death rate. Intubation of either retinoid on day 10 failed to induce a significant increase in the number of litters containing offspring with malformations, and the embryonic death rate declined to control values. The malformations induced by administration of either retinoid were similar, but retinol was always associated with a higher total percentage of malformed offspring. The similar teratogenic profile of these two retinoids may be related to their in vivo biotransformation to all-trans-retinoic acid.

Abnormalities, Drug-Induced↗
PubMed1985

Developmental toxicity of the cyanogenic glycoside linamarin in the golden hamster.

Cassava, a staple food in many tropical countries, has been suspected as a cause of human congenital defects. Ingestion of the material during pregnancy has been reported to induce limb defects, microcephaly, open eye, and growth retardation in rats. Linamarin is a natural cyanogenic glycoside that occurs in high concentrations in cassava. In the present study, pregnant hamsters received an oral dose of 70,100, 120 or 140 mg/kg linamarin or an equivalent volume of isotonic saline during the early primitive streak stage of gestation. A dose of 120 or 140 mg/kg of the glycoside was associated with an increased incidence of vertebral and rib anomalies as well as the production of encephaloceles in the offspring. These larger doses of linamarin also resulted in obvious maternal toxicity. Linamarin treatment had no effect on fetal body weight, ossification of fetal skeletons, embryonic mortality, or litter size. Although ingestion of the cyanogenic glycoside was associated with a significant teratogenic response, the effects occurred only at doses that elicited signs of maternal intoxication.

Abnormalities, Drug-Induced↗
PubMed1985

Comparative pharmacokinetics of vitamin A (retinol) in rats and hamsters.

The absorption and elimination of all-trans-retinol in the plasma of rats and hamsters were studied after an oral dose of 45 mg/kg body weight. The hamsters exhibited a higher pretreatment mean circulating retinol concentration than rats maintained on an identical diet. The increase in plasma retinol after a single oral dose was much greater in hamsters than rats. The area under the plasma concentration v. time curve was approximately 60% greater for rats than for hamsters. The elimination half-times for rats were much longer than for hamsters. Plasma retinol uptake and disappearance were consistent with a two-compartment open model with first-order absorption.

Administration, Oral↗
PubMed1985

Cranioschisis aperta with encephaloschisis in cephalothoracopagus hamster twins.

The results of gross and histopathological study of a near-term male hamster exencephalic lateral cephalothoracopagus are presented. There was minimal duplication of the internal organs to the point of division at the abdomen. The appendicular skeleton was relatively unaffected by the severe malformations of the axial skeleton. The studies suggested that the lateral relationship of the skull to the spinal columns was a consequence of the presence of two embryonic neural tubes; the chordomesodermal systems of the right and left twins apparently contributed the tissues for the right and left cephalic neural folds, respectively. Anomalies of the vertebral bodies and neural arches were not related to failure of closure of the neural tube as there was no evidence for rachischisis in either body half. Rather, the anomalous axial skeletal elements were apparently the result of competing fields of development by two chordomesodermal systems. The twins were recovered from a dam maintained on a diet consisting of 80% cassava, a cyanide-containing staple consumed by humans in tropical countries. Because the numbers of resorbed implantation sites and malformed litermates were low and the failure to produce conjoined twins in other litters recovered from dams given cassava diets, it appears unlikely that the malformation was related to the composition of the diet.

Abnormalities, Severe Teratoid↗
PubMed1984

A probit analysis program for the personal computer.

Application software for economical and convenient calculation of median effective doses, confidence limits, potency ratios and slopes of quantal dose-response curves using a microcomputer is presented. The PASCAL language program is stored on diskette and it is compatible with many commercially available microcomputer systems. The program will simultaneously calculate the parameters for up to 20 different treatments and a total of 100 doses. Comparisons between the results of calculations of the LD50 of thiopental in mice using the PASCAL program, a modem-accessed commercially available probit analysis program and three, widely accepted manual calculation methods are made. The results of calculations of parallelism and the potency ratio between thiopental and phenobarbital-induced death in mice are shown.

Animals↗
PubMed1984

Prenatal and developmental toxicology of arsenicals.

A variety of species, including the human, have been shown to be susceptible to the embryotoxic effects of inorganic arsenic. Malformations of the axial skeleton, neurocranium, viscerocranium, eyes, and genitourinary systems as well as prenatal death followed a bolus dose of trivalent or pentavalent inorganic arsenic. Trivalent arsenic was more teratogenic than pentavalent arsenic; in contrast, the methylated metabolites of arsenic possessed only limited teratogenic activity. Administration of inorganic arsenic to mammals results in concentration of arsenic within the placenta and small amounts are deposited within the embryo. Studies concerning the pathogenesis of arsenic-induced axial skeletal lesions revealed early failure of neural fold elevation and a subsequent, persistent failure of closure of the neural tube. Physical factors, drugs and heavy metals may modify the response to a teratogenic dose of inorganic arsenic. Medical problems associated with industrial or agricultural arsenicalism are most often typified by chronic exposure; future studies should emphasize those routes of administration and types of exposure that are characteristic of arsenic intoxication.

Abnormalities, Drug-Induced↗
PubMed1984

Structure-activity relationships of retinoids in developmental toxicology. I. Studies on the nature of the polar terminus of the vitamin A molecule.

The teratogenic activities of all-trans-retinoyl fluoride, all-trans-3-retinylidene-2,4-pentanedione, all-trans-2-retinylidene-1,3-cyclopentanedione, all-trans-2-retinylidene-5,5-dimethyl-1,3-cyclohexanedione, all-trans-2-retinylidene-5-p-methoxyphenyl-1,3-cyclohexanedione, all-trans-2-retinylidene-1,3-cyclooctanedione, all-trans-5-[2,6-dimethyl-8-(2,6,6-trimethylcyclohexen-1-yl)-1,3, 5,7-octatetrae n-1-yl]tetrazole, ethyl all-trans-9-(exo-2-bicyclo[2.2.1.]heptyl)-3,7-dimethyl-2,4,6,8- nonatetraenoate, ethyl all-trans-4-[2-methyl-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,3- butadien-1-yl]benzoate, 13-cis-N-(4-hydroxyphenyl)retinamide, and 13-cis-N-(2-hydroxyethyl)retinamide were determined in the hamster and compared with that of all-trans-retinoic acid. Administration of a single oral dose of the retinoids failed to induce signs of the hypervitaminosis A intoxication syndrome in any of the dams, and the maternal weight gain was not significantly different from the vehicle control value, except following intubation of the retinamides where maternal weight gain was significantly depressed. All of the retinylidene 1,3-diketones studied here were devoid of significant teratogenic activity. The retinamides failed to induce either an elevated mean litter frequency of malformed fetuses or a syndrome of anomalies similar to that induced by administration of an equimolar dose of all-trans-retinoic acid. All of the other retinoids induced a syndrome of malformations similar to that induced by administration of all-trans-retinoic acid and were associated with a significant increase in the number of litters containing one or more malformed fetuses and an elevated mean litter frequency of malformed fetuses. The teratogenic activity in the hamster of this series of retinoids was independent of structural modifications in either the beta-cyclogeranylidene ring or the polyene chain of the molecule. The results of the present study suggest that the changes in teratogenic activity associated with structural modification of vitamin A at C15 were primarily dependent upon the presence of or biotransformation to a free carboxyl or a moiety with an equivalent pKa at C15, not upon the molecular size of the substituent or the stereochemical position about C13. Since major structural modifications of vitamin A were made without the substantial loss of teratogenic activity, the structural requirements of retinoids for induction of terata were not extraordinarily exacting.

Animals↗
PubMed1984

Teratogenic dose-response relationships of etretinate in the golden hamster.

Etretinate (Ro 10-9359; Tigason; 4-methoxy-2,3,6-trimethylphenyl analog of retinoic acid, ethyl ester) was evaluated for teratogenic activity in the Syrian golden hamster. Groups of pregnant hamsters were given a single oral dose of 2.8-88 mg/kg etretinate during the early primitive streak stage of gestation. No signs of maternal intoxication were observed in any of the hamsters given the retinoid and maternal body weight changes throughout gestation were not significantly different from those of the vehicle-treated group. Etretinate administration was associated with a dose-dependent increase in the incidence and severity of malformations. The average fetal body weight was significantly less in litters recovered from dams given 44 or 88 mg/kg of etretinate when compared to the average body weight of fetuses recovered from dams given an equivalent volume of the vehicle. The average crown-rump lengths also were significantly shorter in fetuses taken from the dams given 44 or 88 mg/kg etretinate as compared to the control group. The malformations induced by etretinate administration were similar to those noted following an oral dose of all-trans-retinoic acid (Willhite and Shealy, 1984). A comparison of the dose-response curves for induction of terata following treatment with etretinate or all-trans-retinoic acid revealed that etretinate was twice as potent as a teratogen in the hamster as all-trans-retinoic acid. Teratogenic activity of etretinate in the hamster was achieved at doses (mg/kg body wt) used in patients at current clinical therapeutic levels.

Abnormalities, Drug-Induced↗
PubMed1984

Comparative pharmacokinetics of trypan blue in female Sprague-Dawley and Long-Evans rats.

Administration of trypan blue to pregnant Sprague-Dawley or Long-Evans rats, during an identical stage of embryogenesis, has been associated with malformations in 97 and 17% of the offspring, respectively (Gunberg, Anat. Rec. 1958, 130, 310). In the present study the comparative pharmacokinetics of trypan blue in the two strains were investigated. Female Sprague-Dawley and Long-Evans rats were injected sc with 10 mg trypan blue/rat [0.5 ml 2% (w/v) trypan blue in distilled water]. Blood samples were collected from the post-orbital plexus at times ranging from 5 min to 480 hr after dosing. The peak serum concentration of trypan blue was greater in Sprague-Dawley rats. Pharmacokinetic analyses of concentrations of trypan blue in serum resulted in fitting a two-compartment open model, with first order absorption, for both strains. Elimination of trypan blue from the central compartment was faster in Sprague-Dawley rats. This phenomenon was associated with a net movement out of the central compartment, predicted by the ratio of intercompartment rate constants. It is possible that the reported differences between the two strains in the teratogenic effects of trypan blue could be attributable, in part, to these observed pharmacokinetic dissimilarities.

Absorption↗
PubMed1984

Developmental toxicology of retinylidene methyl nitrone in the golden hamster.

A single oral dose in pregnant hamsters of 50, 75 or 100 mg/kg of all-trans-retinylidene methyl nitrone, a retinoid with potential cancer chemo-preventive properties, resulted in a significant increase in the number of litters containing abnormal offspring. An elevated mean litter frequency of malformed offspring was also observed following doses of 50 mg/kg or greater of the retinoid. Doses of 12.5 mg/kg or greater were associated with a significant increase in embryonic death. Intubation of the retinoid failed to induce signs of illness in any of the pregnant hamsters and the maternal weight gain of the treated animals was not significantly different from that of dams given an equivalent volume of the vehicle. The dysmorphic syndrome induced by treatment with all-trans-retinylidene methyl nitrone during the early primitive streak stage of gestation was identical to that induced by treatment with all-trans-retinoic acid. The teratogenic effects of all-trans-retinylidene methyl nitrone may be associated with biotransformation of the parent nitrone in the acidic environment of the stomach to all-trans-retinoic acid.

Administration, Oral↗
PubMed1984

Dose-response relationships of retinol in production of the Arnold-Chiari malformation.

A single oral dose of 5000, 10 000, 15 000, 20 000 or 30 000 I.U. vitamin A alcohol (retinol) on the eighth day of gestation in the pregnant hamster resulted in the production of the Arnold-Chiari malformation types I and II in 0, 6.6, 57, 56 and 85%, respectively, of all fetuses examined. The pattern and severity of the malformations of the chondrocranium and viscerocranium changed as the dose of retinol was increased. The smallest dose of retinol used in the present study which induced gross terata in hamsters was approximately 11 times greater than the highest oral daily dose of retinol used in clinical cancer chemoprevention trials.

Abnormalities, Drug-Induced↗
PubMed1984

Amelioration of embryotoxicity by structural modification of the terminal group of cancer chemopreventive retinoids.

An oral dose of all-trans-retinoic acid or 13-cis-retinoic acid in the pregnant [Lak:LVG(SYR)] hamster caused a dose-dependent increase in malformations in the offspring, but an equivalent dose of all-trans-N-ethyl retinamide or 13-cis-N-ethyl retinamide failed to result in embryotoxicity. The present results show that structural modification of the retinoid skeleton can produce compounds that retain cancer chemopreventive activity but that lack the teratogenic activity common to many synthetic and naturally occurring forms of vitamin A. The results indicate that in the case of the retinoids the two kinds of activity--interference with the process of carcinogenesis and interference with embryonic development--may be divorced.

Abnormalities, Drug-Induced↗
PubMed1983

Benomyl.

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Animals↗