Tissue distribution of cytochrome P450 3A (CYP3A) in brushtail possums (Trichosurus vulpecula) exposed to Eucalyptus terpenes.

We evaluated the distribution pattern of a specific xenobiotic metabolizing enzyme, cytochrome P450 3A (CYP3A) in the common brushtail possum (Trichosurus vulpecula). Western blot studies using CYP3A antibodies were used to compare CYP3A levels in the intestine, liver, kidney, brain, testes and adrenal gland in possums fed diets with and without a mixture of terpenes. Possums appear to produce at least 3 different CYP3A-like isoforms that are differentially expressed in various tissues. The liver and duodenum produce all three isoforms (CYP3A P1, P2, P3), the jejunum only produces CYP3A P1, the ileum, kidney, testes and adrenal only produce CYP3A P2 and the brain only produces CYP3A P3. Terpene treatment did not alter relative levels of isoforms present in any tissue type. This study is the first to identify the presence and differential expression of several CYP3A-like isoforms in a variety of tissues of a wild mammalian herbivore. Data suggest that CYP3A-like enzymes are not induced by terpenes. However, the wide distribution of CYP3A-like isoforms in a variety of tissues, suggests that these enzymes are an important mechanism for metabolism in possums and may contribute to the high tolerance possums have to a wide range of xenobiotics.

A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree.

Familial hypercholesterolemia results from mutations in the low-density lipoprotein (LDL) receptor or apolipoprotein B genes. We have previously reported the identification of a Utah autosomal-dominant hypercholesterolemia pedigree (kindred 1173) that did not show linkage to either of these loci (Hunt et al. 2000). Expansion of the pedigree and increased marker density within the region of interest have resulted in a multipoint LOD score of 9.6 and enabled us to decrease the size of the linked region to approximately 7.5 Mbp. In addition, we were able to identify additional families sharing the same microsatellite haplotype. While all haplotype carriers in kindred 1173 (K1173) are affected, the haplotype carriers within the newly identified families are unaffected, suggesting that the causal mutation in K1173 had occurred after divergence of these pedigrees from a common ancestor. Mutation screening of genes in the region identified a single nucleotide variant (G-->T) present on the K1173 haplotype that was not present on the same haplotype in the other kindreds. This variant results in a D374Y missense change in the gene PCSK9.