Each cell contains both maternal and paternal copies of all genes except those that reside on the sex chromosomes. However, because of a phenomenon termed genomic imprinting, not all genes are biallelically expressed. Imprinted genes play an important role in embryogenesis and re‐cently have also been shown to be mechanistically involved in carcinogenesis. The growing list of im‐printed genes implicated in tumor formation in‐cludes both a growth factor gene, insulin‐like growth factor 2 (IGF2), and a receptor gene, mannose 6‐ phosphate/insulin‐like growth factor 2 receptor (M6P/IGF2R). Elevated expression of IGF2 is often found in tumors, and loss of imprinting is one mechanism by which its expression is deregulated. The M6P/IGF2R functions in the inactivation of the mitogen IGF2 and in the activation of the growth inhibitor, transforming growth factor beta. Recently, a high frequency of loss of heterozygosity with concomitant mutations in the remaining allele has been shown to occur at the M6P/IGF2R locus (i.e., 6q26‐q27) in both human liver and breast tumors, suggesting that this gene functions as a tumor suppressor. Expression of the M6P/IGF2R gene is biallelic in most humans but is monoallelic in mice. This species difference in M6P/IGF2R gene imprinting provides one plausible explanation for the enhanced sensitivity of mice to tumor formation. Furthermore, these findings suggest that species differences in the imprinted status of genes mechanistically involved in tumor formation should be factored into human carcinogenesis risk assessment models when extrapolating results from mice to humans.—De Souza, A. T., Yamada, T., Mills, J. J., Jirtle, R. L. Imprinted genes in liver carcinogenesis. FASEB J. 11, 60‐67 (1997)

The enteric nervous system (ENS) provides the intrinsic neural control of the gastrointestinal tract (GIT) and regulates virtually all GI functions. Altered neuronal activity within the ENS underlies various GI disorders with stress being a key contributing factor. Thus, elucidating the expression and function of the neurotransmitter systems, which determine neuronal excitability within the ENS, such as the GABA-GABA A receptor (GABA A R) system, could reveal novel therapeutic targets for such GI disorders. Molecular and functionally diverse GABA A Rs modulate rapid GABAergic-mediated regulation of neuronal excitability throughout the nervous system. However, the cellular and subcellular GABA A R subunit expression patterns within neurochemically defined cellular circuits of the mouse ENS, together with the functional contribution of GABA A R subtypes to GI contractility remains to be determined. Immunohistochemical analyses revealed that immunoreactivity for the GABA A R gamma (␥) 2 and alphas (␣) 1, 2, 3 subunits was located on somatodendritic surfaces of neurochemically distinct myenteric plexus neurons, while being on axonal compartments of submucosal plexus neurons. In contrast, immunoreactivity for the ␣4 -5 subunits was only detected in myenteric plexus neurons. Furthermore, ␣-␥2 subunit immunoreactivity was located on non-neuronal interstitial cells of Cajal. In organ bath studies, GABA A R subtype-specific ligands had contrasting effects on the force and frequency of spontaneous colonic longitudinal smooth muscle contractions. Finally, enhancement of ␥2-GABA A R function with alprazolam reversed the stress-induced increase in the force of spontaneous colonic contractions. The study demonstrates the molecular and functional diversity of the GABA A R system within the mouse colon providing a framework for developing GABA A R-based therapeutics in GI disorders.

BackgroundGenetic influences on drug efficacy and tolerability are now widely known. Pharmacogenetics has thus become an expanding field with great potential for improving drug efficacy and reducing toxicity. Many pharmacologically-relevant polymorphisms do show variability among different populations. Knowledge of allelic frequency distribution within specified populations can be useful in explaining therapeutic failures, identifying potential risk groups for adverse drug reactions (ADRs) and optimising doses for therapeutic efficacy. We sought to determine the prevalence of clinically relevant Cytochrome P450 (CYP) 2C8, CYP2C9, and CYP2C19 variants in Ghanaians. We compared the data with other ethnic groups and further investigated intra country differences within the Ghanaian population to determine its value to pharmacogenetics studies.MethodsRFLP assays were used to genotype CYP2C8 (*2, *3, *4) variant alleles in 204 unrelated Ghanaians. CYP2C9*2 and CYP2C19 (*2 and *3) variants were determined by single-tube tetra-primer assays while CYP2C9 (*3, *4, *5 and *11) variants were assessed by direct sequencing.ResultsAllelic frequencies were obtained for CYP2C8*2 (17%), CYP2C8*3 (0%), CYP2C8*4 (0%), CYP2C9*2 (0%), CYP2C9*3 (0%), CYP2C9*4 (0%), CYP2C9*5 (0%), CYP2C9*11 (2%), CYP2C19*2 (6%) and CYP2C19*3 (0%).ConclusionAllele frequency distributions for CYP2C8, CYP2C9 and CYP2C19 among the Ghanaian population are comparable to other African ethnic groups but significantly differ from Caucasian and Asian populations. Variant allele frequencies for CYP2C9 and CYP2C19 are reported for the first time among indigenous Ghanaian population.

Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD), a widespread polychlorinated aromatic hydrocarbon, caused tumors in the liver and other sites when administered chronically to rats at doses as low as 0.01 microgram/kg/day. It functions in combination with a cellular protein, the Ah receptor, to alter gene regulation, and this resulting modulation of gene expression is believed to be obligatory for both dioxin toxicity and carcinogenicity. The U.S. EPA is reevaluating its dioxin risk assessment and, as part of this process, will be developing risk assessment approaches for chemicals, such as dioxin, whose toxicity is receptor-mediated. This paper describes a receptor-mediated physiologically based pharmacokinetic (PB-PK) model for the tissue distribution and enzyme-inducing properties of dioxin and discusses the potential role of these models in a biologically motivated risk assessment. In this model, ternary interactions among the Ah receptor, dioxin, and DNA binding sites lead to enhanced production of specific hepatic proteins. The model was used to examine the tissue disposition of dioxin and the induction of both a dioxin-binding protein (presumably, cytochrome P4501A2), and cytochrome P4501A1. Tumor promotion correlated more closely with predicted induction of P4501A1 than with induction of hepatic binding proteins. Although increased induction of these proteins is not expected to be causally related to tumor formation, these physiological dosimetry and gene-induction response models will be important for biologically motivated dioxin risk assessments in determining both target tissue dose of dioxin and gene products and in examining the relationship between these gene products and the cellular events more directly involved in tumor promotion.

Chronic inflammation and reduced blood levels of omega-3 fatty acids (n−3) are known characteristics of sickle cell disease (SCD).The anti-inflammatory properties of n−3 fatty acids are well recognized. Omega-3 treated (n = 24), hydroxyurea (HU) treated (n = 18), and n−3 untreated (n = 21) homozygous SCD patients (HbSS) and healthy (HbAA) controls (n = 25) matched for age (5-16 years), gender and socioeconomic status were studied. According to age (5-10) or (11-16) years, two or three capsules containing 277.8 mg docosahexaenoic (DHA) and 39.0 mg eicosapentaenoic (EPA) or high oleic acid placebo (41%) were assigned to n − 3 treated and n − 3 untreated groups, respectively. Hydroxyurea treated group was on dosage more than 20 mg/kg/day. The effect of supplementation on systemic and blood cell markers of inflammation was investigated. The n− 3 treated group had higher levels of DHA and EPA (p b 0.001) and lower white blood cell count and monocyte integrin (p b 0.05) compared with the n−3 untreated. No difference was detected between the two groups regarding C-reactive protein, granulocytes integrin and selectin, plasma tumour necrosis factor-α and interleukin-10. The n−3 treated group had lowered nuclear factor-kappa B (NF-κB) gene expression compared to n−3 untreated and HU treated groups (p b 0.05). This study provides evidence that supplementation with n− 3 fatty acids may ameliorate inflammation and blood cell adhesion in patients with SCD.