Biomedical subjects

A M Bleau

Publications and source records attributed to A M Bleau.

4 recordsLinked to original sources

PubMed2001

Cytochrome P450 down-regulation by serum from humans with a viral infection and from rabbits with an inflammatory reaction.

Serum from humans with an upper respiratory viral infection (HS(URVI)) and from rabbits with a turpentine-induced acute inflammatory reaction (RS(TIAR)) reduces the activity of hepatic cytochrome P450 (P450) following 4 h of incubation. The aim of the present study was to assess the effect of HS(URVI) and RS(TIAR) on P450 activity and expression following 24 h of incubation with hepatocytes from control (H(CONT)) and rabbits with a TIAR (H(INFLA)). RS(TIAR) incubated with H(CONT) for 24 h reduced P450 content and activity, and CYP3A6 by 45%, without changing CYP1A1 and 1A2; when incubated with H(INFLA), RS(TIAR) decreased P450 content and activity without affecting CYP1A1 or 1A2. HS(URVI) incubated for 4 h with H(CONT) decreased P450 activity without affecting the amounts of CYP1A1, 1A2, or 3A6, although when incubated for 24 h, P450 activity and CYP3A6 amount decreased. HS(URVI) incubated with H(INFLA) for 4 h reduced P450 content and activity, and incubated for 24 h reduced activity, P450 content, and amount of CYP1A1 and 1A2 proteins. The present study demonstrates that 1) the effect of RS(TIAR) and HS(URVI) depends upon the susceptibility of the hepatocyte, i.e., H(CONT) or primed H(INFLA); 2) P450 down-regulation is preceded by a decrease in P450 activity; 3) the nature of the inflammatory reaction determines the repercussions on P450 activity and expression; and 4) CYP3A6 is more vulnerable than CYP1A1 and 1A2 to the down-regulation provoked by an inflammatory challenge.

Animals↗

PubMed2000

Genetic correction of sickle cell disease: insights using transgenic mouse models.

Sickle cell disease is a hereditary disorder characterized by erythrocyte deformity due to hemoglobin polymerization. We assessed in vivo the potential curative threshold of fetal hemoglobin in the SAD transgenic mouse model of sickle cell disease using mating with mice expressing the human fetal Agamma-globin gene. With increasing levels of HbF, AgammaSAD mice showed considerable improvement in all hematologic parameters, morphopathologic features and life span/survival. We established the direct therapeutic effect of fetal hemoglobin on sickle cell disease and demonstrated correction by increasing fetal hemoglobin to about 9-16% in this mouse model. This in vivo study emphasizes the potential of the SAD mouse models for quantitative analysis of gene therapy approaches.

Anemia, Sickle Cell↗

PubMed2000

Cytochrome P450 inactivation by serum from humans with a viral infection and serum from rabbits with a turpentine-induced inflammation: the role of cytokines.

Serum from humans with an acute upper respiratory viral infection and from rabbits with turpentine-induced inflammation reduce the catalytic activity of hepatic cytochrome P450 (P450). The aim of this study was to identify the serum mediators responsible for the decrease in P450 activity. Rabbit and human sera were fractionated by size exclusion chromatography and the fractions tested for their ability to reduce the activity and amount of P450 after 4 h of incubation with hepatocytes from turpentine-treated rabbits (H(INF)). Rabbit and human sera decreased P450 activity by around 40% without any change in the amount of CYP1A1 and 1A2 apoproteins. In rabbit serum, the fraction containing proteins of M(r) 23-15 kDa decreased P450 content by 41%, but did not alter the amount of the apoproteins. Anti-IL-6 antibody added to the M(r) 23-15 kDa fraction restored P450 content to 97% of control values, while anti-IL-1beta, TNF-alpha and IFN-gamma antibodies had no effect. Supporting the role of IL-6, incubation of H(INF) in the presence of IL-6 for 4 h reduced P450 content by 40%. In human serum, the fraction containing proteins of M(r) >95 kDa lowered P450 content by 43% without modifying the amounts of CYP1A1/2. Neutralization experiments showed that IFN-gamma, IL-6, and IL-1beta contributed to the decrease in P450 content. In conclusion, the present results demonstrate that IL-6, and IFN-gamma, IL-6 and IL-1beta are the serum mediators released in vivo by a turpentine-induced inflammatory reaction in the rabbit and an upper respiratory viral infection in humans, respectively, inactivating hepatic P450.

Animals↗

PubMed2000

Role of reactive oxygen intermediates in the decrease of hepatic cytochrome P450 activity by serum of humans and rabbits with an acute inflammatory reaction.

Serum of rabbits with a turpentine-induced acute inflammatory reaction (RS(INFLA)) and serum of humans with a viral infection (HS(INF)) were previously shown to diminish hepatic cytochrome P450 (P450) content and activity. To document the role of reactive oxygen intermediates in the serum-mediated decrease in P450 content and activity, hepatocytes of rabbits with an acute inflammatory reaction (H(INFLA)) were incubated with RS(INFLA) and HS(INF) for 4 h, and total P450 content (spectrally measurable P450), P450 activity (assessed by estimating the formation of theophylline metabolites), and amount of CYP1A1, CYP1A2, and CYP3A6 proteins were measured. RS(INFLA) or HS(INF) decreased P450 content and activity without affecting the amount of CYP1A1 and -1A2 H(INFLA). Exposure of H(CONT) or H(INFLA) to hydrogen peroxide (0.01-1.0 mM) and sodium nitroprusside (0.01-1.0 mM) produced a dose-dependent decrease in P450 content and in the formation of theophylline metabolites without modifying the amount of CYP1A1 and CYP1A2, whereas lipid peroxidation increased. Incubation of L-NAME (0.05-1.0 mM), dimethylthiourea (6.25-50 mM), or N-acetylcysteine (0.01-1.0 mM) with H(INFLA) partially prevented the decrease in P450 content and activity and the increased lipid peroxidation induced by RS(INFLA) and HS(INF). On the other hand, 3-amino-1,2,4-triazole (10-100 mM) or diethyldithiocarbamate (1.0-10 mM) potentiated RS(INFLA)- and HS(INF)-mediated decreases in P450 content and activity and the increase in lipid peroxidation, without affecting the amount of CYP1A1 or -1A2; DL-buthionine-(S,R)-sulfoximine (2.5-25 mM) potentiated only the inhibition of 1,3-dimethyluric acid formation. It is concluded that reactive oxygen intermediates are implicated in the decrease of H(INFLA) P450 content and activity induced by 4 h of exposure to RS(INFLA) or HS(INF).

Acute-Phase Reaction↗