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Biomedical subjects

G L Biagi

Publications and source records attributed to G L Biagi.

At least 19 recordsLinked to original sources
PubMed2005

CYP superfamily perturbation by diflubenzuron or acephate in different tissues of CD1 mice.

This work aimed to investigate whether the insecticide acephate (125 or 250 mg/kg b.w.) or diflubenzuron (752 or 1075 mg/kg b.w.), two of the most widely used pesticides worldwide, impairs CYP-linked murine metabolism in liver, kidney and lung microsomes after repeated (daily, for three consecutive days) i.p. administration. The regio- and stereo-selective hydroxylation of testosterone was used as multibiomarker of different CYP isoforms. Both gender and tissue specific effects were observed. Lung was the most responsive tissue to induction by lower diflubenzuron dose, as exemplified by the marked increase of testosterone 7alpha-hydroxylation (CYP2A) (up to 13-fold) in males. Higher dose produced a generalized inactivation. At the lower dose acephate induced 6beta- (CYP3A1/2, liver) as well as 2beta- (CYP2B1/2, kidney) hydroxylase activities ( approximately 5 and approximately 4-fold increase, respectively) in males. In females, a marked suppression of the various hydroxylations was observed. At 250 mg/kg of acephate, animals did not survive. Induction of the most affected isoforms was sustained by immunoblotting analysis. Corresponding human CYP modulations might disrupt normal physiological functions related to these enzymes. Furthermore, the co-mutagenic and promoting potential of these pesticides, phenomena linked to CYP upregulation (e.g. increased bioactivation of ubiquitous pollutants and generation of oxygen free radicals) are of concern for a more complete definition of their overall toxicological potential.

Animals↗
PubMed2003

The clinical role of cytochrome p450 genotypes in Helicobacter pylori management.

OBJECTIVE: The aim of this pharmacogenomics study was to investigate the influence of different cytochrome P450 (CYP) genotypes in Helicobacter pylori eradication therapy. METHOD: The study involved 143 consecutive Italian Caucasian patients with H. pylori infection diagnosed and treated with 1-wk triple therapy according to European Helicobacter Pylori Study Group guidelines. Using human genomic DNA, CYP2C19 (*2 and *3) and CYP3A4 alleles (*1B, *2, and *3) were evaluated by polymerase chain reaction-restriction fragment length polymorphism assays and confirmed by sequencing the amplicons. RESULT: According to the endoscopy-based gold standard, 93 patients achieved H. pylori eradication. Regarding CYP2C19 genotype, the 50 patients who remained infected were all homozygous or heterozygous extensive metabolizers (homEM or hetEM). Carriers of homEM fared significantly less well than those of hetEM; homEM genotype was also predictive of failure at univariate/multivariate analysis. Carriers of CYP3A4 polymorphisms achieved favorable eradication rates similar to patients bearing CYP2C19. All four patients with single CYP3A4*2 polymorphism achieved eradication, and only 29% (5/17) of all CYP3A4*1B carriers did not achieve eradication. All nine patients carrying CYP3A4 polymorphisms in the CYP2C19 hetEM subgroup were cured, suggesting the possibility of a positive synergism between CYP3A4 and CYP2C19. CONCLUSIONS: This first pharmacogenomics study on the influence of different CYP genotypes on H. pylori therapy suggests that, as in Asian populations, CYP2C19 genotype patterns are probably also relevant in Caucasians receiving H. pylori eradication regimens that include omeprazole. The possibility of a favorable drug interaction mediated by CYP2C19 and CYP3A4 requires investigation.

Adult↗
PubMed1999

beta-carotene as enhancer of cell transforming activity of powerful carcinogens and cigarette-smoke condensate on BALB/c 3T3 cells in vitro.

We report the ability of beta-carotene (betaC) to affect the cell transforming activity of 3-methylcholanthrene (3-MCA), benzo(a)pyrene (B(a)P) and cigarette-smoke condensate (TAR) in an in vitro medium-term (approximately 8 weeks) experimental model utilizing BALB/c 3T3 cells. Different experimental schedules were performed either in the presence or absence of betaC: (i) cultures treated for 72 h with each chemical (acute treatment), (ii) cultures grown in presence of each chemical for the whole period of the experiment (chronic treatment). These procedures suggested a possible cocarcinogenic potential of the carotenoid following interactions with other chemicals mimicking continuous human exposition to several xenobiotics. Although the pigment did not show any cell transforming potential when tested alone either in acute or chronic treatment, it did augment that of other tested agents. Induction of cell transformation by B(a)P was markedly enhanced by the presence of this carotenoid in either acute or chronic treatment. Only in presence of betaC, was TAR able to significantly act as a cell transforming agent in prolonged, chronic treatment of cultures. Enhanced cell transformation activity could be due to the boosting effect of betaC on P450 apparatus. Indeed, elsewhere we have found that the latter increased the ratio of formation of diol epoxide carcinogenic metabolites of B(a)P as well as other carcinogens present in TAR. By contrast, no differences of cell transforming activity of 3-MCA, an ultimate carcinogen, were seen either in the presence or absence of betaC under the various experimental conditions. These data, which are in keeping with the cocarcinogenic potential of betaC, may help to explain the unexpected lung cancer increases obtained in chemoprevention trials in heavy smokers supplemented with the isoprenoid. Our findings also highlight the potential risk to humans derived from interactions among xenobiotics present in the environment.

3T3 Cells↗
PubMed1999

The many consequences of chemical- and genetic-based modulation of drug metabolizing enzyme activities.

The induction or inhibition of the metabolizing enzyme activities by a great deal of substances (including drugs) influence their toxicological or pharmacological outcomes as well as that of other xenobiotics or drugs to which human is simultaneously exposed. The dual bioactivating/detoxificating nature of both phase I and phase II enzymes poses such modulation as an unavoidable unhealthy phenomenon. Therefore, the proposed strategies in preventive medicine which foresee boosting or depressing enzymatic effects such as those in the field of cancer chemoprevention, should be carefully reconsidered before their credibility would be compromised. As the phenotypic features, genetic polymorphisms leading to the occurrence of high or low metabolizers in the population, each at high risk to certain forms of toxicity, behave as a sort of "constitutive" enzymatic modulation. Thus, considering the double-edged sword nature (detoxi-toxicant) of these catalysts towards ubiquitous environmental pollutants, the search for individual susceptibility by means of the genotypic analysis represents a very intriguing problem. However, the knowledge of the "overall" metabolic fingerprint associated to the phenotypic analysis in a single person could offer an interesting way to (partially) control human risk by making suitable (well aimed) modifications of determined life-styles (e.g. stop smoking or drinking) or particular dietetic practices (e.g. stop eating high cooked meat or fish) as well as selecting personalised drug adjustments by physicians either in terms of dosage or fitting drug.

Biological Availability↗
PubMed1998

Enzyme evolution and cancer: hypothesis why natural carcinogens are more potent than synthetic ones.

A great deal of evidence shows that carcinogen induced mutations in human cancers point towards natural rather than man-made agents. Here, we propose a model based on the premise that the evolutionary pressure of nature renders natural carcinogens more potent than artificial ones, present in equal concentration, by suitably modifying kinetic parameters of carcinogen metabolizing enzymes. Enzymes are evolved to bind the transition state of substrates more strongly than substrates themselves, thus obtaining more elevate values of the specificity constant kcat/Km (Ksp). Natural selection optimizing the catalytic power at the proper substrate concentration by suitable raising the Km values, reduce the Gibbs standard activation energy (G(0#)), accelerating the conversion of natural precarcinogens to potent carcinogens. Conversely, "man-made" carcinogens, since the last century in the biosphere, are converted to active metabolites at a lower rate than natural chemicals and the slower rate of activation would allow protective enzymes and DNA repair machinery more time to clean up the damage.

Carcinogens↗
PubMed1998

Cancer chemoprevention: some complications and limitations.

Chemopreventive strategies are very attractive and have earned serious consideration as a potential means of controlling cancer incidence. However, the use of some anti-initiating entities (enzyme inducers or inhibitors) devised to reduce tumor initiation is controversial. Indeed, considering the double-edged-sword (activating or detoxifying) nature of drug metabolizing enzymes, any attempt to modulate such catalysts by dietary components (including drugs) may lead to cancer risk.

Animals↗
PubMed1997

Development of basal and induced testosterone hydroxylase activity in the chicken embryo in ovo.

1. The sensitivity of the developing embryo to xenobiotics is highly dependent on the expression of metabolizing enzymes including cytochromes P450 (CYP). In the present study, therefore, the ontogeny of the CYP-dependent system in the chick was investigated with testosterone hydroxylase activity as a marker of CYP expression. 2. Chicken embryo livers were assayed for basal and phenobarbitone (PB)-induced regio- and stereo-selective testosterone hydroxylase activity, from the first appearance of the liver as a discrete organ at 5 days of incubation through day 10 posthatching. In addition, whole embryo preparations were assayed at 3 and 4 days of incubation. 3. Whereas testosterone 16 beta-hydroxylase and androst-4-ene-3, 17-dione-linked activities were expressed during all stages of embryonic development, testosterone 6 alpha-, 6 beta-, 7 alpha- and 16 alpha-hydroxylase activities were observed only in basal embryos from 8 days of incubation. Furthermore, testosterone 2 alpha- and 2 beta-hydroxylase activities were detected exclusively from 10 days of incubation onward. All activities increased steadily throughout development as did the responsiveness of the embryonic liver to PB induction. 4. A typical pattern of development with a higher activity from 10 to 14 days of incubation (testosterone 16 alpha-, 7 alpha-, 6 alpha- and 2 beta-hydroxylase activities; up to 4.1 +/- 0.3 pmol mg-1 protein min-1 at 13 days of incubation for testosterone 7 alpha-hydroxylase) or shifted to 14 to 18 days of incubation (testosterone 6 beta-, 2 alpha- and 16 beta-hydroxylase activities: up to 56.6 +/- 1.4 pmol mg-1 protein min-1 at 16 days of incubation for testosterone 6 beta-hydroxylase) was observed. There was a tendency towards an increased activity for all activities around hatching, specifically from 19 days of incubation to 4 days posthatching (up to 1,759.3 +/- 179.4 pmol mg-1 protein min-1 at 1 day posthatching for androst-4-ene-3,17-dione-linked activity). 5. The highest level of PB-induced enzyme activity was observed for testosterone 2 alpha-hydroxylase activity (95.14 +/- 7.35 and 660.19 +/- 45.27 pmol mg-1 protein min-1) at 12 days of incubation and day 3 posthatching, respectively. Except for testosterone 2 alpha- and 2 beta-hydroxylase activities at 3 to 4 days of incubation, all metabolites were detectable during the first period of organogenesis in the presence of PB. 6. The use of highly specific substrates, studies on the immunoinhibition of metabolism by polyclonal antibodies raised against highly purified rat CYPs, and the use of selective inhibitors seemed to reveal a wide pleiotropic response with the possible presence in liver of PB-treated chickens of CYP1A together with CYP2HI/H2, CYP2E and CYP3A.

Animals↗