Mortality and cancer incidence were studied in the National Registry for Radiation Workers in, relative to earlier analyses, an enlarged cohort of 174 541 persons, with longer follow-up (to 2001) and, for the first time, cancer registration data. SMRs for all causes and all malignant neoplasms were 81 and 84 respectively, demonstrating a 'healthy worker effect'. Within the cohort, mortality and incidence from both leukaemia excluding CLL and the grouping of all malignant neoplasms excluding leukaemia increased to a statistically significant extent with increasing radiation dose. Estimates of the trend in risk with dose were similar to those for the Japanese A-bomb survivors, with 90% confidence intervals that excluded both risks more than 2 -3 times greater than the A-bomb values and no raised risk. Some evidence of an increasing trend with dose in mortality from all circulatory diseases may, at least partly, be due to confounding by smoking. This analysis provides the most precise estimates to date of mortality and cancer risks following occupational radiation exposure and strengthens the evidence for raised risks from these exposures. The cancer risk estimates are consistent with values used to set radiation protection standards.

P-glycoprotein, a member of the ATP-binding cassette transporter family, is able to confer resistance on tumors against a large number of functionally and chemically distinct cytotoxic compounds. Several recent investigations suggest that P-glycoprotein contains multiple drug binding sites rather than a single site of broad substrate specificity. In the present study, radioligand-binding techniques were used to directly characterize drug interaction sites on P-glycoprotein and how these multiple sites interact. The drugs used were classified as either 1) substrates, which are known to be transported by P-glycoprotein (e.g., vinblastine) or 2) modulators, which alter P-glycoprotein function but are not themselves transported by the protein (e.g., XR9576). Drug interactions with P-glycoprotein were either competitive, at a common site, or noncompetitive, and therefore at distinct sites. Based on these data, we can assign a minimum of four drug binding sites on P-glycoprotein. These sites fall into two categories: transport, at which translocation of drug across the membrane can occur, and regulatory sites, which modify P-glycoprotein function. Intriguingly, however, some modulators interact with P-glycoprotein at a transport site rather than a regulatory site. The pharmacological data also demonstrate that both transport and regulatory sites are able to switch between high- and low-affinity conformations. The multiple sites on P-glycoprotein display complex allosteric interactions through which interaction of drug at one site switches other sites between high- or low-affinity conformations. The data are discussed in terms of a model for the mechanism of transport by P-glycoprotein.

This paper is dedicated to the memory of our friend and colleague Andreas Schmidlin P-glycoprotein (P-gp) is an ABC (ATP-binding cassette) transporter, which hydrolyses ATP and extrudes cytotoxic drugs from mammalian cells. P-gp consists of two transmembrane domains (TMDs) that span the membrane multiple times, and two cytoplasmic nucleotide-binding domains (NBDs). We have determined projection structures of P-gp trapped at different steps of the transport cycle and correlated these structures with function. In the absence of nucleotide, an~10 A Ê resolution structure was determined by electron cryo-microscopy of two-dimensional crystals. The TMDs form a chamber within the membrane that appears to be open to the extracellular milieu, and may also be accessible from the lipid phase at the interfaces between the two TMDs. Nucleotide binding causes a repacking of the TMDs and reduction in drug binding af®nity. Thus, ATP binding, not hydrolysis, drives the major conformational change associated with solute translocation. A third distinct conformation of the protein was observed in the post-hydrolytic transition state prior to release of ADP/P i . Biochemical data suggest that these rearrangements may involve rotation of transmembrane a-helices. A mechanism for transport is suggested.