Mammalian cytosolic glutathione S-transferases (GSTs; EC 2.5.1.18) form a supergene family consisting of four distinct families, named alpha, mu, pi and theta. In humans one member of the mu class gene family (GSTM1) has been shown to be polymorphic and is only expressed in 55-60% of individuals. Previous studies have shown a possible link with the null phenotype and susceptibility to cancer, in particular to lung cancer. In this study we genotyped individuals with breast, bladder and colorectal cancer. A total of 490 individuals with cancer were studied, and consisted of 97 bladder, 197 breast and 196 colorectal cancers. No significant differences were observed in the frequency of nulled individuals in bladder or breast cancer patients when compared with a control population of 225 individuals. However, a significant excess of nulled individuals were seen in colorectal cancer: 56.1% compared with the control group value of 41.8%. This was shown to be highly significant depending on the site of the tumours and > 70% of individuals with a tumour in the proximal colon were GSTM1 nulled. This is an approximately 2-fold increase in colon cancer risk in these individuals.

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The antitumor drugs of the anthraquinone group are widely used agents in the treatment of a variety of human neoplasms. However, their clinical effectiveness is limited by several factors, among which dose-dependent cardiotoxicity is of great importance. Numerous data indicate that the cardiac effects of these drugs are the consequence of one-electron transfer from reduced nucleotides to atmospheric oxygen. This process is catalyzed primarily by NADH dehydrogenase, NADPH cytochrome P450 reductase, and xanthine oxidase, and leads to the formation of reactive oxygen species. In our previous studies we have shown that the NADH dehydrogenase catalyzed electron transfer phenomenon is correlated with the affinity of anthraquinone drugs to the enzyme. In this work data are presented on the ability of compounds belonging to several structural types of anthraquinone cytostatics (sugar- and quinone-modified derivatives of DR and ADR, and anthracenedione compounds) to stimulate free radical formation in the above three enzymatic systems. It has been shown that the three oxidoreductases exhibit different structural requirements with respect to their substrate properties for anthraquinones. Therefore, evaluation of the structural factors determining the ability of anthraquinone compounds to generate active oxygen species cannot be limited to a single oxidoreductase system but must include all types of enzymatic systems involved in the catalysis of one-electron transfer reactions.

In this paper, we evaluate methodologies and null mouse models used to study drug transporter function in vitro and in vivo. P-glycoprotein and MRP null mice have been used to examine many aspects of xenobiotic distribution and bioavailability. Their advantage over conventional models is that they allow the exclusion of transporters from a particular process; however, they cannot be used to study the activity of the transporter that has been deleted. Use of humanized mice permits a logical progression from phenomena in wild-type mice via the effects of removing the mouse transporter to the consequences of replacing it with its human counterpart.

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The frequency distributions of the 0-8 h urinary metabolic ratios of debrisoquine and mephenytoin were measured in 111 healthy, unrelated Sinhalese resident in Sri Lanka. Blood samples were taken from 77 of these subjects for CYP2D6 genotyping.Bimodality in the distribution of the logio debrisoquine/4-hydroxydebrisoquine ratio was not evident from visual inspection and by kernel density analysis. The results of genotyping indicated that 82% of the population were either homozygous for the wild-type CYP2D6 gene or heterozygous for the wild type allele and the whole gene deletion. Eighteen per cent of the Sinhalese population were heterozygous for the CYP2D6B mutation and the wild-type allele. All of these genotypes give rise to the extensive metaboliser phenotype in white Caucasians. No CYP2D6A mutations were identified and no individuals who were homozygous for the mutant alleles were detected, which is in accord with an absence of phenotypic poor metabolisers of debrisoquine. The mutant CYP2D6 allele frequency in Sinhalese (9%) is only half that observed in white Caucasians. The S/R-mephenytoin ratio ranged from 0.09 to 2.27 (median 0.38). By visual inspection and kernel density analysis the distribution of the S/R-mephenytoin ratio was bimodal and, using a value of 0.9 for the antimode, 16 (14%) subjects were poor metabolisers. In conclusion, the prevalence of the poor metaboliser phenotype in Sinhalese appears much lower for debrisoquine and higher for mephenytoin than in white Caucasians. These findings are similar to those observed in Indians living in Bombay and in Oriental populations.

The anatomical basis of symptomatic hemidystonia. Brain 1985;108:463-83. 2 Boisen E. Torticollis caused by an infraten-torial tumour: three cases. Br J Psychiatry 1979;134:306-7. 3 Isaak K, Cohen JA. Post-traumatic torticollis.