Biomedical subjects

P Bodénez

Publications and source records attributed to P Bodénez.

6 recordsLinked to original sources

PubMed2001

Genetic repeat polymorphism in the regulating region of CYP2E1: frequency and relationship with enzymatic activity in alcoholics.

BACKGROUND: Differences in the regulatory region of the CYP2E1 gene could be responsible for the interindividual variation in the cytochrome P-450 2E1 (CYP2E1) involved in ethanol oxidation. Recently, a polymorphic repeat sequence in the human gene was described between -2178 and -1945 base pairs. Its frequency seemed to vary among different ethnic populations, and it was suspected to be related to an increased inducibility to further ethanol intake. In the study reported here, the frequency of this polymorphism was investigated in a white French population. Its relationship with the previously described PstI/RsaI or DraI CYP2E1 polymorphisms, alcoholism, alcoholic liver disease, and inducibility of CYP2E1 by ethanol was examined. METHODS: The polymorphic region was characterized by polymerase chain reaction in 103 controls, 148 alcoholic subjects without liver diseases, and 98 others with liver cirrhosis. By using in vivo chlorzoxazone (CHZ) metabolism, CYP2E1 phenotype was assessed in 36 non-ethanol-induced subjects (17 controls and 19 withdrawn alcoholics) and in 14 ethanol-induced subjects (10 controls after ingestion of 0.8 g/kg ethanol and four alcoholics with 100 g of daily intake). This phenotype was expressed as the 6-hydroxy CHZ/CHZ ratio. RESULTS: The rare allele frequency was found to be 1.58% in whites (n = 349). Neither significant association with alcoholism or alcoholic liver diseases, nor relationship with the PstI/RsaI polymorphism, was observed. But the DraI polymorphism was more frequent among the heterozygous subjects when compared with wild-type homozygous ones (p < 0.05). The CYP2E1 phenotype was similar in wild-type homozygotes and in heterozygotes at the constitutive level, as well as after induction with ethanol. CONCLUSIONS: Our data suggest that CYP2E1 repeat polymorphism does not seem to constitute a major factor for interindividual differences in CYP2E1 expression and susceptibility to alcohol-related disorders in whites.

Adult↗

PubMed2000

Cytochrome P-450 2E1 activity and oxidative stress in alcoholic patients.

As cytochrome P-450 2E1 (CYP2E1) induction was related to oxidative stress in experimental models, the aim of this study was to investigate the relationship between CYP2E1 activity and markers of oxidative stress in 40 alcoholic patients entering a rehabilitation programme. Plasma oxidized proteins, lipid peroxides (LPO) and antibodies against hydroxyethyl radical (HER) or malondialdehyde (MDA) adducts were assessed as markers of the production of free radicals, whereas vitamin E levels were evaluated as a marker of the antioxidant defence. CYP2E1 activity was determined by using the 6-hydroxychlorzoxazone:chlorzoxazone blood metabolic ratio, 2 h after drug intake. This ratio was increased by 4-fold in alcoholics, compared to non-alcoholic patients, and was correlated with daily intake of ethanol, carbohydrate-deficient transferrin, and blood alcohol level at the time of admission to hospital. Plasma levels of LPO and oxidized proteins were slightly increased (20%) in alcoholic patients when compared with the control group, whereas those of vitamin E were found to be slightly decreased (by 18%). Antibodies against HER or MDA adducts showed a very significant increase. However, when alcoholic patients were divided into two groups according to low or high CYP2E1 induction, no significant difference was observed in the variation of these parameters, except for anti-HER adducts antibodies. Therefore, our study confirms the main involvement of CYP2E1 in HER production. By contrast, CYP2E1 does not appear to be the main factor responsible for the oxidative stress occurring during human chronic alcoholism. Free radicals from other sources may therefore contribute significantly to the generation of this oxidative stress.

Adult↗

PubMed1996

Cytochromes P4502E1 and P4501A1 genotypes and susceptibility to cirrhosis or upper aerodigestive tract cancer in alcoholic caucasians.

Genetic polymorphisms of various cytochromes P450 have recently been described and could be implicated in the individual susceptibility of alcoholics to ethanol-related diseases. Rsal and Dral polymorphisms of CYP2E1 and Mspl polymorphism of CYP1A1 were studied in 260 controls and 511 alcoholic patients, without any clinical symptoms (n = 202) or with various ethanol-related diseases (n = 309), such as liver cirrhosis (n = 110), esophageal cancer (n = 62), upper aerodigestive tract cancer (n = 96), and other miscellaneous diseases (n = 41). Frequencies of the mutated alleles were found to be 2.5% (Rsal), 7.9% (Dral), and 8.7% (Mspl) in controls; 4%, 14.1%, and 12% in alcoholics without clinical symptoms; and 3.1%, 12.5%, and 11.2% in alcoholics with ethanol-related diseases. The only significant difference was found in the Dral polymorphism, whose frequency was enhanced in alcoholics with (p < 0.05) or without ethanol-related diseases (p < 0.01) when compared with controls. No differences were found between alcoholics without clinical symptoms and alcoholics with cirrhosis, esophageal cancer, or upper aerodigestive tract cancer. However, in liver cirrhosis and in ethanol-related cancers, the rare Dral-C allele was three times less frequent in patients under the age of 45 than in older patients, suggesting a protective role for this allele. In conclusion, our data indicate that the aforementioned mutations do not play a critical role in the development of cirrhosis, esophageal cancer, or upper aerodigestive tract cancers in Caucasians.

Adult↗

PubMed1995

Cytochrome P450 2E1 genotype and chlorzoxazone metabolism in healthy and alcoholic Caucasian subjects.

Susceptibility to cancer or ethanol-related liver diseases may be associated with a large variability in cytochrome P450 2E1 activity. This variability may be of genetic origin or reflect environmental factors. To test the role of genetics, the phenotype and genotype of this enzyme were determined in 42 non-alcoholic and 74 alcoholic patients hospitalized for detoxification treatment. Chlorzoxazone metabolism was used to assess CYP2E1 phenotype. Restriction length fragment polymorphisms with Rsa I or Pst I, and Dra I endonucleases were used to determine the two mutant alleles, Pst I/Rsa I-c2 and Dra I-C. A significant gender difference in basal CYP2E1 activity was observed in non-smoking controls (p < 0.05) but not in alcoholics or smokers. Subjects heterozygous for the C or c2 mutated allele did not show any difference in CYP2E1 activity at the basal level, compared with the wild type homozygotes. Conversely, patients with the mutated genotype appeared less inducible than the others after ethanol induction (p < 0.01).

Adult↗

PubMed1995

Decrease in cytochrome P4502E1 as assessed by the rate of chlorzoxazone hydroxylation in alcoholics during the withdrawal phase.

To evaluate cytochrome P4502E1 (CYP2E1) induction in alcoholics, the ratio of the concentrations of 6-hydroxychlorzoxazone (6-OH-CHZ) and chlorzoxazone (CHZ) was measured in blood 2 hr after CHZ ingestion using a HPLC method. This ratio was determined in controls and in alcoholic patients after 1, 2, 3, 4, 5, 8, and 21 days withdrawal. It was found to be 0.34 +/- 0.03 in 30 controls and 1.05 +/- 0.14 in 41 alcoholic patients within 2 days following ethanol withdrawal. This ratio decreased rapidly during withdrawal as attested by the short half-life of CYP2E1, which was found to be 2.5 days. Patients tested for CHZ metabolism after 8 or 21 days alcohol abstinence displayed the same ratio as controls [0.35 +/- 0.03 (n = 28) and 0.31 +/- 0.03 (n = 34), respectively]. No correlation was observed between gamma-glutamyltransferase, carbohydrate-deficient transferrin values, the amount of alcohol consumed/day, and the 6-OH-CHZ/CHZ ratio. There was no influence of smoking on the rate of CHZ hydroxylation, because smokers displayed the same ratio as nonsmokers [0.33 +/- 0.025 (n = 62) and 0.33 +/- 0.02 (n = 30), respectively]. The CHZ hydroxylation ratio seems to be a good reflection of the hepatic and extrahepatic CYP2E1 activity in humans.

Adult↗

PubMed1988

Acetaldehyde adducts with haemoglobin: determination of acetaldehyde released from haemoglobin by acid hydrolysis.

Acetaldehyde, the first metabolite of ethanol, reacts with haemoglobin in vitro to produce acetaldehyde-haemoglobin adducts. Some clinical studies on the minor haemoglobins have suggested that these adducts may be formed in people abusing alcohol. Under hydrolysis of haemoglobin, with oxalic acid at 100 degrees C in sealed vials, some acetaldehyde was released and then specifically determined by HPLC. The kinetics of hydrolysis were studied using haemoglobin previously labelled with 14[C] acetaldehyde. The maximum liberation of 14 [C] acetaldehyde was obtained after 3 hr 30 min hydrolysis and this time factor was then utilized in the analysis of alcoholic and control haemoglobin. Thus, we have confirmed the formation of acetaldehyde haemoglobin adducts in vivo. It must be noted that the released acetaldehyde corresponds only to an index of the stable adducts. The levels were higher in alcoholics than in controls (1.417 +/- 0.171 and 1.295 +/- 0.139 nmol/mg Hb, respectively, P less than 0.001). In conclusion, this marker is not a convenient tool for the monitoring of alcohol exposure levels because of the low differences between alcoholic and control haemoglobins.

Acetaldehyde↗