Genetic determinants of drug-induced agranulocytosis: potential risk of olanzapine?

Whether or not olanzapine causes bone marrow toxicity is still a matter of debate. In spite of pre-marketing and post-marketing clinical trials, and although there have been no cases in animals of olanzapine-induced neutropenia or agranulocytosis, the risk of bone marrow toxicity cannot be excluded. The present paper addresses the following questions: what is the potential background of drug-induced agranulocytosis? Are there any case reports supporting the view that olanzapine has relevant bone marrow toxicity? What strategies might be helpful in identifying the pathological mechanisms underlying this side effect?

Paraoxonase 1 mutations in a Turkish population.

Human serum paraoxonase 1 (PON1) catalyzes the hydrolysis of certain organophosphate pesticides and nerve gases and so may alter significantly an individual's susceptibility to the toxicity of these chemicals. Moreover, PON1 hydrolyzes lipid peroxides complexed to low density lipoproteins (LDL) and therefore it was suggested that PON1 may be one of the genes that is involved in the pathogenesis of cardiovascular diseases. Its activity shows interindividual and interethnic variability.

Pitfalls in N-acetyltransferase 2 genotyping.

In recent times, an increasing number of different haplotypes of the arylamine N-acetyltransferase 2 gene are reported. Since most of the various alleles are defined by linkages of commonly known hereditary point mutations, some confusion may occur when the mutation pattern revealed by genotyping should be addressed correctly to defined haplotypes. Moreover, problems take place when different nomenclatures are incorrectly transferred.

Association of arylamine N-acetyltransferases NAT1 and NAT2 genotypes to laryngeal cancer risk.

Genetically polymorphic xenobiotic metabolizing enzymes are supposed to be host factors for an individual's cancer susceptibility. A total of 255 laryngeal cancer patients was genotyped for NAT1 and NAT2 and compared with 510 reference individuals, matched by age and gender. NAT1 genotypes (NAT1*3, *4, *10, and *11 ) were found equally distributed between cases and control individuals.

A1/A2 polymorphism of glycoprotein IIIa and association with excess procedural risk for coronary catheter interventions: a case-controlled study.

Background: A five-fold increase in risk of stent thrombosis in carriers of A1/A2 (Leu33Pro) polymorphism of glycoprotein Illa has been described. Whether this increased procedural risk applies to other coronary interventions is unknown. We investigated the role of A1/A2 polymorphism as a putative risk factor.

High benzo[a]pyrene diol-epoxide DNA adduct levels in lung and blood cells from individuals with combined CYP1A1 MspI/Msp-GSTM1*0/*0 genotypes.

Levels of anti-benzo[a]pyrene diol-epoxide DNA adducts were analysed by high-pressure liquid chromatography/fluorimetric detection in non-tumorous lung tissues from 20 lung cancer patients and in white blood cells from 20 polycyclic aromatic hydrocarbon exposed coke oven workers. All were current tobacco smokers. CYP1A1 mutations (MspI at 6235 nt, Ile-Val462) and GSTM1 deletion polymorphisms in each individual were analysed in genomic DNA by PCR/restriction fragment length polymorphism.

Polymorphisms in xenobiotic conjugation and disease predisposition.

Low activity of arylamine N-acetyltransferase 2 (slow NAT2) was consistently associated with urinary bladder cancer risk. The increased cancer risk attributable to slow NAT2 was more significant when taking gene-environment interactions and gene-gene interactions into account. In urinary bladder, slow NAT2 was no risk factor in subjects who never smoked but became increasingly relevant with increasing lifetime dose of tobacco smoke expressed by an odds ratio of 2.

High frequency of CYP1A1 mutations in a Turkish population.

The frequency distribution of four cytochrome P4501A1 (CYP1A1) gene mutations was investigated in 271 Turks from southeast Anatolia by polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP) assay. Allelic linkage of those mutations was proven by peptide nucleic acid-mediated PCR clamping. Mutation ml (T6235C) forming an MspI restriction site in the 3'-flanking region occurred with 18.

Arylamine N-acetyltransferase (NAT2) genotypes in a Turkish population.

A group of 303 unrelated Turkish subjects from south-east Anatolia was genotyped for seven NAT2 mutations by polymerase chain reaction-restriction fragment length polymorphism. Genotypes associated with slow acetylation were identified in 57.4% (95%-confidence limits, 51.

CYP1A1 mutations 4887A, 4889G, 5639C and 6235C in the Polish population and their allelic linkage, determined by peptide nucleic acid-mediated PCR clamping.

Mutations in the CYP1A1 gene were investigated in 324 Polish children and adolescents using PCR/RFLP. Mutation T6235C (m1) occurred in 6.6% of alleles (95& confidence limits 4.

N-Acetyltransferase 2 (NAT2) and Glutathione S-Transferase µ (GSTM1) in Bladder-cancer Patients in a Highly Industrialized Area.

The study was designed to assess occupational and non-occupational risk factors in patients with urothelial carcinomas in an area of former coal, iron, and steel industries, with special regard to the impacts of polymorphic enzymes involved in the metabolism of aromatic amines (N-acetyltransferase 2, NAT2) and of polycyclic aromatic hydrocarbons (glutathione S-transferase µ, GSTM1). Inpatients with bladder cancer (n = 179) were interviewed for occupations ever engaged in for more than six months, and for bladder cancer risk factors in general. NAT2 was phenotyped by high-pressure liquid chromatography of caffeine metabolites in urine.

[Clinical relevance of acetylator phenotyping in 196 urothelial tumor patients].

A total of 196 patients with urothelial tumours were phenotyped for N-acetyltransferase 2 by the molar ratio of two caffeine metabolites excreted in urine. The proportion of "slow" acetylators, who are genetically predisposed to urothelial tumours if they have been exposed to aromatic amines in the past, in the entire group was 55%, within the range in a normal population. Among 40 patients with assumed former occupational exposure to aromatic amines, 65% were "slow" acetylators.

Polymorphic enzymes of xenobiotic metabolism as modulators of acquired P53 mutations in bladder cancer.

Occurrence or specific types of mutations found in oncogenes or tumor suppressor genes may partially be determined by activities of toxifying or detoxifying enzymes, such as glutathione S-transferases (GST) M1 and T1, arylamine N-acetyltransferase (NAT2), microsomal epoxide hydrolase, and the cytochrome P-450 enzymes 2D6, 1A1, 2A6, and 2E1. In an explorative observational study, 69 bladder cancer patients were analysed for acquired mutations in the p53 tumor suppressor gene. The same patients were studied for the polymorphic traits of xenobiotic metabolism given above which were characterized from blood cell DNA by molecular methods.

A C4887A polymorphism in exon 7 of human CYP1A1: population frequency, mutation linkages, and impact on lung cancer susceptibility.

This study reports a C-->A transversion at position 4887 in exon 7 of cytochrome P4501A1 (CYP1A1), resulting in a threonine-asparagine exchange in codon 461. The polymorphism is located directly beside the known codon 462-Ile/Val mutation (m2) near the heme binding region. The C4887A mutation leads to the loss of a BsaI cleavage site, which allows analysis.

Occupational history and genetic N-acetyltransferase polymorphism in urothelial cancer patients of Leverkusen, Germany.

Objectives: The study was designed to realize possible shifts in the ratio of slow to fast acetylators within a group of 196 urothelial cancer patients in an area with earlier benzidine production.

Methods: The subjects were interviewed for occupational and nonoccupational risk factors. The patients were phenotyped for N-acetyltransferase 2 (NAT2) by Grant's caffeine test.

Homozygous rapid arylamine N-acetyltransferase (NAT2) genotype as a susceptibility factor for lung cancer.

The polymorphic arylamine N-acetyltransferase (NAT2) is supposed to be a susceptibility factor for certain malignancies. A phenotyping study in 389 lung cancer patients revealed a similar distribution of rapid and slow acetylators by the caffeine test to that in 657 reference subjects (odds ratio, 1.05; 95% confidence limits, 0.

Combined analysis of inherited polymorphisms in arylamine N-acetyltransferase 2, glutathione S-transferases M1 and T1, microsomal epoxide hydrolase, and cytochrome P450 enzymes as modulators of bladder cancer risk.

Foreign compound-metabolizing enzymes may modify the risk of chemically induced cancer. We wanted to examine enzymes with putative relevance in urinary bladder cancer using molecular genetic analyses of heritably polymorphic enzymes. Arylamine N-acetyltransferase (NAT2); glutathione S-transferases (GSTs) M1 and T1; microsomal epoxide hydrolase; and cytochrome P-450 enzymes (CYP) 1A1, 2C19, 2D6, and 2E1 were analyzed in 374 cases and in 373 controls in a hospital-based case-control study in Berlin.

Determination and allelic allocation of seven nucleotide transitions within the arylamine N-acetyltransferase gene in the Polish population.

The frequency of various genotypes of arylamine N-acetyltransferase (NAT2) was investigated in 248 Polish unrelated children. Allele-specific polymerase chain reaction (PCR) was applied for mutation at 341 nucleotide (nt) of NAT2 coding sequence and PCR/restriction fragment length polymorphism for the other mutations. Genotypes coded for slow acetylation in 62.

Arylamine N-acetyltransferase (NAT2) mutations and their allelic linkage in unrelated Caucasian individuals: correlation with phenotypic activity.

The polymorphic arylamine N-acetyltransferase (NAT2; EC 2.3.1.

Effects of a heterogeneous set of xenobiotics on RNA synthesis of yeast cells.

Previously the toxicity of 45 heterogeneous environmental chemicals on growth and membrane functions in Saccharomyces cerevisiae and Chinese hamster ovary (CHO) cells (Cascorbi et al., 1993) was examined. In this study the inhibitory effects of the same set of chemicals on yeast RNA synthesis rate, measuring [2-14C]uracil uptake during cell proliferation are presented.

Polymorphisms in the human CYP1A1 gene as susceptibility factors for lung cancer: exon-7 mutation (4889 A to G), and a T to C mutation in the 3'-flanking region.

Genetic differences in the metabolism of carcinogens may codetermine individual predisposition to cancer. Cytochrome P-4501A1 (CYP1A1) metabolically activates precarcinogens in cigarette smoke, such as benzo(a)pyrene, which is also an inducer of CYP1A1. Two point mutations have been reported, m1 in the 3'-flanking region (6235T to C), and m2 within exon 7 (4889A to G), the latter leading to an isoleucine to valine exchange.

Effects of a heterogeneous set of xenobiotics on growth and plasma membranes of mammalian and fungal cell cultures.

A comparison of the toxicity of 45 selected, heterogenous substances on two test organisms of different taxonomic levels, the yeast Saccharomyces cerevisiae and Chinese hamster ovary (CHO) cells, was made. In addition, effects on the yeast plasma membrane-integrated H(+)-ATPase and on the CHO adenosine uptake system were investigated. For all test systems, log EC50 values highly correlated with log EC20 values.