Biomedical subjects

F Guéraud

Publications and source records attributed to F Guéraud.

3 recordsLinked to original sources

PubMed1999

In vivo involvement of cytochrome P450 4A family in the oxidative metabolism of the lipid peroxidation product trans-4-hydroxy-2-nonenal, using PPARalpha-deficient mice.

Trans-4-hydroxy-2-nonenal (HNE) is a potent cytotoxic and genotoxic compound originating from the peroxidation of n-6 polyunsaturated fatty acids. Its metabolism has been previously studied in the rat (Alary et al. 1995. Chem. Res. Toxicol., 8: 35-39). In addition to major urinary mercapturic derivatives, some polar urinary metabolites were isolated and could correspond to hydroxylated compounds. 4-Hydroxynonenoic acid (HNA), resulting from the oxidation of the HNE carbonyl group, is a medium chain fatty acid and its omega-hydroxylation might be hypothesized. Therefore, the involvement of the CYP 4A family isoenzymes in the metabolism of [3H]HNE has been investigated in vivo using inducer treatments (fibrates) in wild-type or in peroxisome proliferator-activated receptor alpha (PPARalpha)-deficient mice. In wild-type mice, but not in PPARalpha (-/-) mice, fibrate treatments resulted in an increase of two urinary metabolites characterized, after HPLC purifications and mass spectrometry analyses, as the omega-hydroxylated metabolite of HNA, i.e., 4,9-dihydroxy-2-nonenoic acid, and its oxidized form, 4-hydroxy-2-nonene-1,9-dicarboxylic acid. The formation of the latter is correlated accurately to laurate hydroxylase activity studied concurrently in microsomes prepared from the liver of these animals. Basal levels of these two metabolites were measured in urine of normal and PPARalpha-deficient mice. These results are in accord with an implication of the P450 4A family in the extended oxidative metabolism of 4-HNE.

Aldehydes↗

PubMed1998

Glucuronidation: a dual control.

1. Glucuronidation is a major detoxication process catalyzed by uridine diphosphate glucuronosyltransferases. 2. The amount of enzyme can be modulated by numerous foreign compounds, such as common chemical inducers already implicated in the induction of other detoxication enzymes. 3. Hormones such as thyroid hormones or growth hormone also are implicated in the control of glucuronidation. 4. Because glucuronidation enzymes (isozymes) are anchored in the endoplasmic reticulum membrane, with their active site likely being located on the lumenal side of the membrane, the membrane environment of these enzymes was shown to modulate their functional state as evaluated by the conjugating activity per enzymatic molecular unit. 5. In accord with a first, previously proposed model, it seems that this modulation can be attributed to different conformational states of the enzymes, depending on the physicochemical state of the membrane. 6. In accord with a second model, the membrane may act as a barrier between the enzymes and the cosubstrate UDP-glucuronic acid, which is a polar and charged molecule synthesized in the cytosol. This would imply a transporting process for this molecule through the reticulum membrane, which has been characterized in vitro and could be of importance in vivo. 7. Glucuronidation is under the control of a dual regulation, by means of a specific isozyme expression level and by the modulation of their functional state.

Animals↗

PubMed1997

Hepatic microsomal membrane lipidic composition and growth hormone effect in adult male rat: evidence for a 'feminization' process of total phospholipid fatty acid pattern.

Growth hormone (GH) effects on fatty acid composition and on delta5-, delta6-, delta9-desaturase and palmitic acid elongation activities were studied in male rat hepatic microsomes. Sham-operated and hypophysectomized animals were injected with two different dosages of GH, mimicking either the male or female GH secretion pattern. Half the hypophysectomized animals received thyroxine and cortisol in concentrations chosen to compensate for the lack of thyroid hormones and glucocorticoids. GH, administered to sham-operated or to cortisol/thyroxine-treated hypophysectomized rats resulted in an increase in stearic and arachidonic acid proportions, while palmitic acid percentage was decreased. Total monounsaturated fatty acids were dramatically reduced by this treatment. DeltaA-desaturase and palmitic acid elongation activities were increased by GH treatment, while delta9-desaturase activity was decreased. These GH effects on desaturation and elongation activities could explain the modifications in microsomal fatty acid composition. Hypophysectomy markedly altered the fatty acid composition by reducing arachidonic and stearic acid proportions and increasing the linoleic acid proportion, while delta9-, delta5-desaturase and palmitic acid elongation activities were decreased. Restoration of most of the fatty acid proportions to control values was realized in hypophysectomized animals with a cortisol/thyroxine replacement administered alone or together with the low dosage of GH mimicking the male secretion pattern. High GH dosage produces essentially a 'feminization' process of the fatty acid composition of the hepatic microsomal membrane in male rats when compared to that of females.

Animals↗