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Biomedical subjects

M T Landi

Publications and source records attributed to M T Landi.

At least 19 recordsLinked to original sources
PubMed1999

Human cytochrome P4501A2.

CYP1A2, a member of the cytochrome P450 superfamily (CYPs), is involved in the metabolic activation of several carcinogens, among them aromatic and heterocyclic amines, nitroaromatic compounds, mycotoxins and estrogens. Several drugs are also metabolized by CYP1A2. Individual differences in CYP1A2 activity may thus influence individual susceptibility to cancer risk and the therapeutic efficacy of some drugs. In humans, CYP1A2 has been detected only in the liver, where it seems to be regulated by at least two mechanisms, one controlling constitutive levels of expression and another regulating inducibility. Wide interindividual differences in CYP1A2 activity have been described. They may be due to factors such as gender, race, genetic polymorphisms, and exposure to inducers. Higher activity has been shown in men than in women. Wide variation across racial/ethnic groups has been reported. Overall, slow and intermediate CYP1A2 metabolizers represent about 50% of Caucasians, while their frequency in Japanese subjects seems to be much lower. No nucleotide differences that could explain the phenotypic variability of the CYP1A2 gene have been found in any exons, exon-intron junctions, or 5'-flanking regions of the gene. However, two genetic variants have been identified which seem to be associated with CYP1A2 inducibility only. Induction of CYP1A2 activity has been reported as a consequence of cigarette smoking, dietary factors, several drugs, chronic hepatitis, and exposure to polybrominated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin. Several epidemiological studies have been conducted into the relationship between CYP1A2 activity, alone or in combination with other CYPs, and cancer risk. In the absence of a genotypic assay, only the CYP1A2 phenotype can be assessed at present. Many compounds have been tested as in vitro probes to assess CYP1A2 activity in humans. Currently, caffeine has the best potential for use in epidemiological studies: metabolites of caffeine after coffee consumption are measured as an index of CYP1A2 activity. Variable results have been obtained with caffeine-based methods, the use of some caffeine metabolite ratios having given bimodal or trimodal distributions while others have suggested normal or unimodal distributions. Although the epidemiological studies are limited because only phenotyping data are available, there is a suggestion of increased risk of colon cancer and bladder cancer in subjects with rapid CYP1A2 activity. A higher level of 4-aminobiphenyl-haemoglobin adducts has also been found in moderate smokers with rapid CYP1A2 phenotype than in subjects with slow activity.

Biotransformation↗
PubMed1998

2,3,7,8-Tetrachlorodibenzo-p-dioxin plasma levels in Seveso 20 years after the accident.

In 1976, near Seveso, Italy, an industrial accident caused the release of large quantities of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) into the atmosphere, resulting in the highest levels of the toxicant ever recorded in humans. The contaminated area was divided into three zones (A, B, R) corresponding to decreasing TCDD levels in soil, and cohort including all residents was enumerated. The population of the surrounding noncontaminated area (non-ABR) was chosen as referent population. Two decades after the accident. plasma TCDD levels were measured in 62 subjects randomly sampled from the highest exposed zones (A and B) and 59 subjects from non-ABR, frequency matched for age, gender, and cigarette smoking status. Subjects living in the exposed areas have persistently elevated plasma TCDD levels (range = 1.2-89.9 ppt; geometric mean = 53.2 and 11.0 ppt for Zone A and Zone B, respectively). Levels significantly decrease by distance from the accident site (p = 0.0001), down to general population values (4.9 ppt) in non-ABR, thus validating the original zone classification based on environmental measurements. Women have higher TCDD levels than men in the entire study area (p = 0.0003 in Zone B; p = 0.007 in non-ABR). This gender difference persists after adjustment for location within the zone, consumption of meat derived from locally raised animals, age, body mass index, and smoking. There is no evidence for a gender difference in exposure, so variation in metabolism or elimination due to body fat or hormone-related factors may explain this finding. Elevated TCDD levels in women may contribute to adverse reproductive, developmental, and cancer outcomes.

Accidents, Occupational↗
PubMed1997

Dioxin exposure and cancer risk: a 15-year mortality study after the "Seveso accident".

Dioxin (2,3,7,8-tetrachlorodibenzo-para-dioxin, or TCDD) is a powerful carcinogen in experimental animals, whereas the evidence in humans is limited. We examined cancer mortality from 1976 to 1991 among residents of Seveso, Italy, which was highly contaminated after an industrial accident. The area was divided into zones with decreasing exposure to dioxin (A = highest, B = lower, R = lowest). The population of a surrounding noncontaminated area was used as a reference group. Zone A was small (11,516 person-years); in that zone, we saw a moderate increase in mortality from digestive cancer among women [relative risk (RR) = 1.5; 95% confidence interval (CI) = 0.5-3.5]. In zone B, we also saw excesses at digestive sites (83,610 person-years), 10 years after the accident. Women had an increased mortality from stomach cancer (RR = 2.4; 95% CI = 0.8-5.7), and men had increased mortality from rectal cancer (RR = 6.2; 95% CI = 1.7-15.9). Hematologic neoplasms were increased. The highest risks were seen in zone B for leukemia in men (RR = 3.1; 95% CI = 1.3-6.4), multiple myeloma in women (RR = 6.6; 95% CI = 1.8-16.8), and Hodgkin's disease in both genders (RR = 3.3; 95% CI = 0.4-11.9 in men; and RR = 6.5; 95% CI = 0.7-23.5 in women). Soft tissue sarcoma was elevated only among zone R males (256,408 person-years; RR = 2.1; 95% CI = 0.6-5.4). We found no increase for all-cancer mortality or major specific sites (for example, respiratory among males, breast among females). The specific excesses that we observed were not explained by bias or confounding, and their association with dioxin exposure is plausible. The follow-up is continuing.

Accidents↗
PubMed1997

Sample collection, processing and storage.

We review issues related to the inclusion of biospecimens in epidemiological studies. Technical advances and the revolution in molecular biology have rendered the use of biomarkers increasingly feasible in epidemiological investigations, however the cost and complexity require interdisciplinary expertise and careful attention to methodological detail in order to ensure validity. The widespread banking of biospecimens for long-term (cohort) studies requires special attention to be paid to these issues. Blood, urine and tumour tissue are in common use in medicine and at least some aspects of sample handling derives directly from this clinical experience, although special considerations apply in the epidemiological setting. An increasingly broad array of biospecimen types have been studied, including exhaled air, nail clippings, buccal cells, saliva, semen, faeces and breast milk. Relevant issues in the processing, storage, shipping, timing of collection and safety procedures are examined in terms of their potential to distort results. The role of carefully developed quality control protocols is emphasized. In order to take full advantage of the opportunities afforded by the use of biomarkers in epidemiological studies, careful attention to biospecimen processing, the stability of the biomarker and the precautions to be taken during transportation and storage of samples is necessary.

Biomarkers, Tumor↗
PubMed1996

Cytochrome P4501A2: enzyme induction and genetic control in determining 4-aminobiphenyl-hemoglobin adduct levels.

Cytochrome P4501A2 (CYP1A2) activity may be related to bladder cancer risk through metabolic activation of aromatic amines, such as 4-aminobiphenyl (ABP), to reactive intermediates that can form DNA and hemoglobin (Hb) adducts. In the context of a study on smoking and bladder cancer risk, 97 healthy male volunteers were investigated. CYP1A2-dependent N-oxidation activity was measured using a molar ratio of urinary caffeine metabolites [(paraxanthine + 1,7-dimethyluric acid)/caffeine] obtained between the fourth and fifth h after drinking a standardized cup of coffee. N-Oxidation activity was induced by blond tobacco smoke, meat consumption the dinner before the test, or more than four cups of coffee a day. The regular use of medication appeared associated with a decrease in N-oxidation levels. Age and alcohol consumption were not related with CYP1A2 activity. A polymorphic distribution of the CYP1A2 and N-acetyltransferase-2 (determined by the caffeine metabolite ratio 5-acetylamino-6-formylamino-3-methyluracil:1-methylxanthine) phenotypes was examined in relation to susceptibility to ABP-Hb adduct formation. Rapid oxidizers and subjects with the combined slow acetylator-rapid oxidizer phenotype showed the highest ABP-Hb adduct levels at a low smoking dose. Blond tobacco smokers exhibited higher adduct levels compared with black tobacco smokers, after adjustment for the quantity of cigarettes smoked. At the highest levels of smoking exposure, no major difference in ABP-Hb adduct levels was found among the different combinations of CYP1A2 and N-acetyltransferase-2 phenotypes. In a subset of only 45 available samples, no association was seen between the ABP-Hb adduct levels and the glutathione S-transferase M1 genotype.

Age Factors↗
PubMed1995

A novel point mutation in a 3' splice site of the NADH-cytochrome b5 reductase gene results in immunologically undetectable enzyme and impaired NADH-dependent ascorbate regeneration in cultured fibroblasts of a patient with type II hereditary methemoglobinemia.

Hereditary methemoglobinemia with generalized deficiency of NADH-cytochrome b5 reductase (b5R) (type II) is a rare disease characterized by severe developmental abnormalities, which often lead to premature death. Although the molecular relationship between the symptoms of this condition and the enzyme deficit are not understood, it is thought that an important cause is the loss of the lipid metabolizing activities of the endoplasmic reticulum-located reductase. However, the functions of the form located on outer mitochondrial membranes have not been considered previously. In this study, we have analyzed the gene of an Italian patient and identified a novel G-->T transversion at the splice-acceptor site of the 9th exon, which results in the complete absence of immunologically detectable b5R in blood cells and skin fibroblasts. In cultured fibroblasts of the patient, NADH-dependent cytochrome c reductase, ferricyanide reductase, and semidehydroascorbate reductase activities were severely reduced. The latter activity is known to be due to b5R located on outer mitochondrial membranes. Thus, our results demonstrate that the reductase in its two membrane locations, endoplasmic reticulum and outer mitochondrial membranes, is the product of the same gene and suggest that a defect in ascorbate regeneration may contribute to the phenotype of hereditary methemoglobinemia of the generalized type.

Amino Acid Sequence↗
PubMed1994

Genetically based N-acetyltransferase metabolic polymorphism and low-level environmental exposure to carcinogens.

The metabolic activation or inactivation of carcinogens varies considerably in human populations, and is partly genetically determined. Inter-individual variability in the susceptibility to carcinogens may be particularly important at low degrees of environmental exposure. Examples of probable human carcinogens that present widespread low-dose exposures are environmental tobacco smoke and diesel exhaust. We have determined levels of DNA adducts in bladder cells and of 4-aminobiphenyl-haemoglobin adducts in 97 volunteers, together with the N-acetylation non-inducible phenotype, the corresponding genotype, and the levels of nicotine-cotinine in the urine. We find that among the slow acetylators, 4-aminobiphenyl adducts were higher than in rapid acetylators at low or null nicotine-cotinine levels, whereas the difference between slow and rapid acetylators was less evident at increasing nicotine-cotinine levels. The N-acetyltransferase genotype is highly predictive of the acetylation phenotype. Our results indicate that the clearance of low-dose carcinogens is decreased in the genetically based slow-acetylator phenotype. Such genetic modulation of low-dose environmental risks is relevant to 'risk assessment' procedures.

Acetylation↗
PubMed1994

Association between CYP1A1 genotype, mRNA expression and enzymatic activity in humans.

Genetic susceptibility factors may play a role in determining adverse effects of exposure to environmental toxins. As a preliminary step to a molecular epidemiological study in a population exposed to 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD), we investigated 20 healthy Caucasian volunteers with a set of putative susceptibility markers including a CYP1A1 Msp I restriction fragment length genetic polymorphism (RFLP), CYP1A1 mRNA expression, and ethoxyresorufin-O-deethylase (EROD) activity in cultured and mitogen-activated blood lymphocytes. Both basal (p = 0.008) and induced (p = 0.0001) EROD activity was significantly higher among persons with a mutation in one or both alleles of the CYP1A1 gene (variant CYP1A1 genotype). Induction in vitro by TCDD significantly increased EROD activity in both variant and wild-type CYP1A1 subjects; however, the absolute increase was greater in subjects with variant genotypes. An additive interaction between genotype and TCDD induction was suggested. Expression of CYP1A1 mRNA, both basal and induced, did not vary significantly across the genotypes.

Adult↗
PubMed1993

Cancer incidence in a population accidentally exposed to 2,3,7,8-tetrachlorodibenzo-para-dioxin.

In 1976, an accident in a plant near Seveso, Italy, exposed the local population to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Persons residing in three zones of decreasing TCDD contamination (A, B, and R) and a reference population were followed up for cancer occurrence in 1977-1986. The most exposed subgroup (A) was small, and only 14 cancer cases were observed. In zone B, hepatobiliary cancer was elevated, especially for those living in the area for > 5 years [relative risk (RR) = 2.8; 95% confidence interval (CI) = 1.2-6.3]. Men exhibited an increase in hematologic neoplasms, most notably lymphoreticulosarcoma (RR = 5.7; 95% CI = 1.7-19.0). Women experienced an increased incidence of multiple myeloma (RR = 5.3; 95% CI = 1.2-22.6) and myeloid leukemia (RR = 3.7; 95% CI = 0.9-15.7). In zone R, the incidence of soft tissue tumors and non-Hodgkin's lymphomas was elevated, particularly among persons living in the area for > 5 years (RR = 3.5; 95% CI = 1.2-10.4 for sarcomas, and RR = 2.0; 95% CI = 1.2-3.6 for non-Hodgkin's lymphomas). Breast cancer among females was below expectations in the most contaminated zones, and a clear deficit for endometrial cancer was observed in zones B and R.

Adult↗
PubMed1992

Mortality of a young population after accidental exposure to 2,3,7,8-tetrachlorodibenzodioxin.

The mortality experience of 19,637 people aged 1-19 years living in an area around Seveso, Italy, contaminated by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) after an accidental explosion in a chemical plant was examined for the period 1976-1986. For comparison, the mortality of the population of nearly 100,000 people living in the surrounding districts was examined. People who left the study area were followed up. Vital status ascertainment was successful in over 99% of the cases. A group of 186 children who contracted chloracne, a reversible marker of TCDD intoxication, shortly after the accident were in the study: none of them died during the observation period. Among the exposed, mortality owing to all causes, to all accidents and to all cancers failed to show major departure from expectations. Five leukaemia deaths were observed, four among males and one among females; the corresponding relative risks were 2.1 (95% confidence interval (CI): 0.7-6.9), and 2.5 (95% CI: 0.2-27.0), respectively. Two lymphatic leukaemias among males yielded a RR = 9.6 (95% CI: 0.9-106.0). Mortality owing to congenital anomalies showed a nearly twofold increase in the contaminated area; however, five out of seven observed cases were born before the accident. Interpretation is limited by the small number of deaths, short latency period and low validity of death certificate information for certain causes, and by the definition of exposure which was based merely on residence. The follow-up is continuing. A cancer morbidity study is in progress.

Adolescent↗
PubMed1992

The debrisoquine metabolic phenotype and DNA-based assays: implications of misclassification for the association of lung cancer and the debrisoquine metabolic phenotype.

Debrisoquine is an antihypertensive drug that is metabolized by cytochrome P4502D6. Deficient metabolism is inherited as an autosomal recessive condition. We previously reported in a case-control study that extensive metabolizers of debrisoquine were at greater risk of lung cancer compared to poor and intermediate metabolizers. Cloning of the gene that encodes P4502D6 (CYP2D6) led to the identification of both wild-type and mutant forms of the gene. Subsequently, a DNA-restriction fragment length polymorphism (RFLP) was identified, and a Southern hybridization-based test was developed in an attempt to define the genotype. When the DNA-RFLP test was applied to stored DNA from our study subjects there was neither a significant association with the metabolic phenotype nor an association with lung cancer. Further work has demonstrated that the wild-type gene, which was characterized by a 29-kb allele, can also contain mutations that result in nonfunctional or absent proteins. When these mutations are present, individuals exhibit the poor or intermediate metabolizer phenotype in spite of the presence of the 29-kb putative wild-type allele. Sequence determination of the mutants led to the development of techniques to exploit the polymerase chain reaction, which, together with Southern analysis, have been reported to detect as many as 95% of poor metabolizers. This technique is being used to examine the association of the extensive metabolizer genotype with lung cancer in the subjects from the case-control study. Preliminary results indicate a weak association between the homozygous wild-type genotype and lung cancer; in contrast, the extensive metabolizer phenotype is strongly associated with lung cancer in this subset.(ABSTRACT TRUNCATED AT 250 WORDS)

Case-Control Studies↗
PubMed1991

Relevance of metabolic polymorphisms to human carcinogenesis: evaluation of epidemiologic evidence.

Genetic modulation of environmental exposures associated with common malignancies (lung and bladder) is an attractive mechanism to explain differential susceptibility to tobacco or occupation related carcinogens in the population. Epidemiologic studies to test the hypothesis of such associations and to evaluate evidence for a causal role for genetic factors in the etiology of chemically-induced tumors are challenging and require the close collaboration of epidemiologists, clinicians and laboratory investigators. In this work we review the evidence for an association of three polymorphisms of drug or xenobiotic metabolism with human cancers. Methodologic considerations and data relevant to evaluating a causal role for each polymorphism are considered. Fair to good support for both an association of the acetylation phenotype with occupationally-related bladder cancer and for an association of the debrisoquine metabolic phenotype and lung cancer is found, although in neither case is the evidence completely convincing. Epidemiologic evidence for the association of aryl hydrocarbon hydroxylase and lung cancer is presently problematic because of difficulties in the assay and subsequent confounding factors. DNA based assays are at various stages of development for each of the genotypes and promise to simplify future studies while introducing new methodologic pitfalls. Further studies in all three areas are warranted as each has important implications for the understanding of the carcinogenic process, etiology and the public health aspects of common malignancies.

Age Factors↗
PubMed1988

Effects of prolonged picotamide therapy on platelet activity in patients with peripheral arterial disease.

An open study was carried out in 14 patients with peripheral arterial disease to investigate the effects of prolonged therapy with picotamide on platelet activity. Patients received daily oral doses of 900 mg picotamide for 1 month, 600 mg per day during the second month and 300 mg per day from the third to the sixth month of the study. Measurements were made before and during therapy of blood coagulation parameters and factors influencing platelet function, i.e. plasma beta-thromboglobulin and serum thromboxane B2. The results showed that there were no significant variations in platelet count, prothrombin time, partially activated thromboplastin time, presence and amount of fibrinogen in blood, and antithrombin III. Examination for fibrinogen degradation products was constantly negative and unaltered during therapy. Although plasma beta-thromboglobulin values did not vary significantly, there was a significant and progressive reduction throughout treatment in serum levels of thromboxane B2.

Aged↗