PubMed Health⌕ Search

Biomedical subjects

F Lepage

Publications and source records attributed to F Lepage.

33 records · Page 2Linked to original sources
PubMedDate not supplied

Mechanisms of mutagenesis in mammalian cells. Application to human thyroid tumours.

Mutations are defined as stable and irreversible modifications of the normal genetic message due to small changes in the number or type of bases, or to large modifications of the genome such as deletions, insertions or chromosome rearrangements. These lesions are due to either polymerase errors during normal DNA replication or unrepaired DNA lesions, which will give rise to mutations through a mutagenic pathway. The molecular process leading to mutagenesis depends largely on the type of DNA lesions. Base modifications, such as 8-oxo-guanine or thymine glycol, both induced by ionizing radiations (IR), are readily replicated leading to direct mutations, usually base-pair substitutions. The 8-oxo-G gives rise predominantly to G to T transversions, the type of mutations found in ras or p53 gene from IR-induced tumors. Bulky adducts produced by chemical carcinogens or UV-irradiation are usually repaired by the nucleotide excision repair (NER) pathway which is able to detect structural distortion in the normal double-strand DNA backbone. These lesions represent a blockage to DNA and RNA polymerases as well as some signal for p53 accumulation in the damaged cell. In the absence of repair, these lesions could be eventually replicated owing to the induction of specific proteins at least in bacteria during the SOS process. The precise nature of the error-prone replication across an unexcised DNA lesion in the template is not fully understood in detailed biochemical terms, in mammalian cells. IR basically produce a very large number of DNA lesions from unique base modifications to single- or double-strand breaks and even complex DNA lesions due to the passage of very high energy particles or to a local re-emission of numerous radicals. The breakage of the double-helix is a difficult lesion to repair. Either it will result in cell death or, after an incorrect recombinational pathway, it will induce frameshifts, large deletions or chromosomal rearrangements. Most of the IR-induced mutations are recessive ones, requiring therefore a second genetic event in order to exhibit any harmful effect and a long latency period before the development of a radiation-induced tumor. The fact that IR essentially induced deletions and chromosomal translocations renders very difficult the use of the p53 gene as a marker for mutation analysis. In agreement with the type of lesions induced by IR, it is interesting to point out that the presence has been observed, in a vast majority of radiation-induced papillary thyroid carcinomas (PTC), of an activated ret proto-oncogene originated by the fusion of the tyrosine kinase 3' domain of this gene with the 5' domain of four different genes. These ret chimeric genes which are due to intra- or inter-chromosomal translocations, were called RET/PTC1 to PTC5. The RET/PTC rearrangements were found in PTC from children contaminated by the Chernobyl fall-out as well as in tumours from patients with a history of therapeutic external radiation, with a frequency of 60-84%. This frequency was only 15% in 'spontaneous' PTC. The type of ret chimeric gene predominantly originated by the accidental or therapeutic IR was different. Indeed, PTC1 was present in 75% of the tumours linked to a therapeutic radiation and PTC3 in 75% of the Chernobyl ones. The other forms of RET/PTC were observed in only a minority of the post-Chernobyl PTC (< 20%). The difference in the frequency of PTC1 and PTC3 in both types of PTC, is statistically significant (P < 10(-5), Fischer's exact test). In two of the post-therapeutic radiation PTC, RET/PTC1 and PTC3 were simultaneously present. A PTC1 gene was also observed in 45% of the adenomas appearing after therapeutic radiation. The long-period of latency between exposure to IR and the appearance of thyroid tumours is probably due to the conversion of a heterozygote genotype of IR-induced mutations to a homozygote one. It will be interesting to use this time lag in accidental or therapeutic-irradiated p

DNA Damage↗
PubMedDate not supplied

The metabolic fate of stiripentol in man.

The metabolism of stiripentol (I), a new antiepileptic drug, was studied in healthy human subjects. Following a single 1200-mg oral dose to one subject, 13 metabolites of I were detected in urine and were identified by GC/MS techniques. The structures of 9 of these metabolites were confirmed subsequently by synthesis of the corresponding reference compounds. The nature of the urinary metabolites of I revealed the operation of five distinct metabolic pathways for this drug, viz. conjugation with glucuronic acid, oxidative cleavage of the methylenedioxy ring system, O-methylation of catechol metabolites, hydroxylation of the t-butyl group, and conversion of the allylic alcohol side-chain to the isomeric 3-pentanone structure. Metabolites of I excreted into urine over 12 hr accounted for the majority (73%) of an acute dose, whereas a further 18% was recovered in feces as the unchanged drug. These findings suggested that the search for additional metabolites would yield only trace amounts. From a quantitative standpoint, the most important pathway of biotransformation of I following both acute and chronic dosing involved opening of the methylenedioxy ring to generate catechol derivatives. This finding probably accounts for the known inhibitory effects of I on the oxidative metabolism of other antiepileptic agents and for the clinically significant drug interactions involving stiripentol.

Adult↗
PubMedDate not supplied

Metabolic chiral inversion of stiripentol in the rat. I. Mechanistic studies.

To study enantioselective aspects of the disposition of stiripentol (STP), a chiral allylic alcohol undergoing development as an antiepileptic drug, a stereoselective synthesis was developed and the configuration of the two enantiomers determined to be (R)-(+) and (S)-(-). Following a single oral dose (300 mg kg-1) of the individual enantiomers to adult male Sprague-Dawley rats, it was found that (R)-STP was transformed extensively to its antipode, whereas little inversion was detected when (S)-STP was administered. Studies on the mechanism of this apparently unidirectional chiral inversion revealed that the phenomenon was dependent on the presence of the side-chain C==C double bond, because the enantiomers of the corresponding saturated alcohol (D2602) did not interconvert in vivo. Experiments with analogs of STP labeled with deuterium or oxygen-18 at the chiral center showed that, whereas the deuterium was retained in vivo, partial loss of the 18O occurred from both enantiomers of the drug. Pretreatment of rats with pentachlorophenol (40 mumol kg-1 i.p.), an inhibitor of sulfation (and possibly other conjugation reactions), led to a marked decrease in the rate of conversion of (R)-STP to its antipode, suggesting that the chiral inversion phenomenon may be mediated, at least in part, by an enantioselective conjugation process.

Administration, Oral↗
PubMedDate not supplied

Metabolic chiral inversion of stiripentol in the rat. II. Influence of route of administration.

As described in the accompanying study, it was found that when the S enantiomer of stiripentol [(S)-STP] was given orally to rats, blood specimens contained only (S)-STP, whereas following administration of an equivalent dose of (R)-STP, both R and S forms of the drug were detected in the systemic circulation. In the present study, we investigated the influence of route of administration on this apparently unidirectional chiral inversion of (R)-STP in the rat. When (R)-STP was given either intravenously (60 mg kg-1) or intraperitoneally (300 mg kg-1), the inversion phenomenon was not observed, indicating that the process must take place presystemically. Following oral administration of either enantiomer of STP, it was found that the drug present at various points along the gastrointestinal tract became progressively enriched in molecules of R configuration, such that the free STP in cecum, large intestine, and feces consisted largely of the R enantiomer, regardless of the configuration of the administered drug. In a parallel in vitro study, it was demonstrated that STP undergoes acid-catalyzed racemization, the rate of which is appreciable at the pH value of the rat stomach (pH approximately 4). On the basis of these observations, it is proposed that the apparent metabolic chiral inversion of (R)-STP results from the combination of at least two factors: 1) partial acid-catalyzed racemization in gastric acid (that affects both enantiomers equally), and 2) enantioselectivity in one or more of the processes involved in the absorption, first pass metabolism or biliary excretion of STP, such that the S isomer appears selectively in the systemic circulation, whereas the R enantiomer is eliminated preferentially in the feces.

Administration, Oral↗
PubMedDate not supplied

[Macroscopic examination of the fresh placenta. Statistical analysis of 1,200 cases. Comparison with maternal and neonatal pathology].

We have examined 1,200 placentas in a fresh state and have compared the results of these examinations with maternal pathology on the one hand and the neo-natal pathology on the other hand. It turns out that most abnormalities of pregnancy are associated in a significant way with the pathological findings in the placenta, and that the good or pathological health of the newborn is significantly associated with the normal of pathological character of the placenta. The principal weakness in this method of examination is the absence of information about infection. This is why it seems important to us to carry out smears from the placenta before examining it macroscopically.

Adult↗