UGT2B7 catalyses the glucuronidation of a diverse range of drugs, environmental chemicals and endogenous compounds. Hence, coding region polymorphisms of UGT2B7 are potentially of pharmacological, toxicological and physiological significance. Two variant UGT2B7 cDNAs encoding enzymes with either His or Tyr at residue 268 have been isolated. The variants, referred to as UGT2B7*1 and UGT2B7*2, respectively, arise from a C to T transversion at nucleotide 802 of the UGT2B7 coding region. Analysis of genomic DNA from 91 unrelated Caucasians and 84 unrelated Japanese demonstrated the presence of the variant alleles encoding UGT2B7*1 and UGT2B7*2 in both populations. However, while there was an approximately equal distribution of subjects homozygous for each allele in the Caucasian population, subjects homozygous for the UGT2B7*1 allele were over 10-fold more prevalent than UGT2B7*2 homozygotes in Japanese. The frequencies of the UGT2B7*1 and UGT2B7*2 alleles were 0.511 and 0.489, respectively, in Caucasians, and 0.732 and 0.268, respectively, in Japanese. The 95% confidence intervals for the two alleles did not overlap between Caucasians and Japanese. Rates of microsomal androsterone, menthol and morphine (3-position) glucuronidation were determined for genotyped livers from Caucasian donors. Statistically significant inter-genotypic differences were not apparent for any of the three substrates. Although the UGT2B7 polymorphism characterized here is probably not associated with altered enzyme activity, the results highlight the need to consider ethnic variability in assessing the consequences of UGT polymorphisms.

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Viral stress-inducible protein p56 is produced in response to viral stress-inducing agents such as doublestranded RNA and interferon, as well as other poorly understood mechanisms of viral infection. It has been shown previously that p56 is able to bind the eukaryotic initiation factor 3e(eIF3e) (p48/Int-6) subunit of the eukaryotic translation initiation factor eIF3 and function as an inhibitor of translation in vitro and in vivo. The exact mechanism by which p56 is able to interfere with protein synthesis is not understood. Based on the known roles of eIF3 in the initiation pathway, we employed assays designed to individually look at specific functions of eIF3 and the effect of p56 on these eIF3-mediated functions. These assays examined the effect of p56 on ribosome dissociation, the eIF3⅐eIF4F interaction, and enhancement of the ternary complex eIF2⅐GTP⅐Met-tRNA i formation. Here we report that p56 is able to inhibit translation initiation specifically at the level of eIF3⅐ternary complex formation. The effect of p56-mediated inhibition was also examined in two different contexts, cap-mediated and encephalomyocarditis virus internal ribosomal entry site-mediated translation. Whereas cap-dependent initiation was severely inhibited by p56, internal ribosomal entry site-mediated translation appeared to be insensitive to p56. Viral stress-inducible protein p56 is a 56-kDa protein that is induced by various agents characteristic of viral infection, such as double-stranded RNA (dsRNA), 1 interferon, and by other less well understood mechanisms associated with viral infection (1). Previous work has characterized the transcriptional regulation of the p56 gene, also known as the 561 gene, ISG56, and IFIT1 (2), as well as the cellular function of the protein in vitro and in vivo (3). p56 belongs to a family of related viral stress-inducible proteins that includes p54, p56, p58, and p60 (4 -8), but the other members of the family are not as well characterized nor are their cellular functions known. Structurally, the only significant feature of p56 is the presence of eight tetratricopeptide (TPR) motifs, motifs shown in other proteins to mediate protein-protein interactions (9). One of the best characterized interactions with p56 identified thus far has been with Int-6/p48 (also known as eIF3e), a subunit of eukaryotic initiation factor 3 (eIF3) (10). Binding of p56 to the eIF3e subunit has been shown to have a functional effect by inhibiting overall cellular translation (3). Whereas the functional effect of p56 has been mapped to TPR motifs 6 -8, the mechanism by which p56 inhibits translation is not known (10).eIF3 is one of the 11 or more initiation factors that are involved in the first stage of protein synthesis in eukaryotes. Mammalian eIF3 is the largest (650 kDa) of all the initiation factors and is composed of 11 or 12 individual subunits eIFaeIFj (11). The exact interactions and stoichiometry of the eIF3 subunits are poorly understood. eIF3 is a multifunctional initiation factor that has been shown to operate a...