Genetic segregation analysis of red blood cell (RBC) histamine N-methyltransferase (HNMT) activity

Methylation is an important pathway in the biotransformation of many drugs, neurotransmitters, and xenobiotic compounds. Histamine N-methyltransferase (HNMT) catalyzes the Nτ-methylation of histamine and structurally related compounds. Measurement of HNMT activity in the RBC makes it possible to access variation in the enzyme activity that may reflect differences in less accessible tissues such as brain. Previously reported high family correlations for RBC HNMT activity suggested that genetic inheritance plays a major role in the regulation of variation in this enzyme. In the present study we completed complex segregation analyses of RBC HNMT activity of 241 individuals in 51 nuclear families that were randomly ascertained through children in the Rochester, Minnesota public school system in order to characterize the mode of inheritance of this important enzyme. We found evidence for major gene influence on the regulation of RBC HNMT activity. Both transformed and untransformed data support the presence of Mendelian major gene segregation, but the gene frequency differences do not indicate a direct correspondence between genotypes inferred from the two sets of analyses. Analyses of the skewed untransformed data indicated the presence of a relatively rare (Q = 0.121) additive major gene for high activity, with the three overlapping genotype distributions representing 77, 21, and 2 % of individuals. Analyses of the normalized transformed data indicated the presence of a common (Q = 0.71) additive major gene for high activity, with the three overlapping genotype distributions accounting for 9, 41, and 50 % of individuals. The analyses of transformed data give the best fit as well as the most parsimonious Mendelian major gene model. However, we cannot rule out the possibility of multiple alleles, and analyses of untransformed data provide some support for a third allele. Molecular studies will be needed to validate and characterize the alleles that regulate RBC HNMT activity levels in humans. © 1993 Wiley-Liss. Inc.     

Interleukin-1 and tumor necrosis factor-mediated regulation of C3 gene expression in human astroglioma cells

In this report, we show that in the human astroglioma cell line D54-MG, both interleukin-1 (IL-1β) and tumor necrosis factor-alpha (TNF-α) enhance C3 gene expression in a time- and dose-dependent manner. Kinetic analysis demonstrates that after 96 h, C3 mRNA levels increase approximately 30-fold and 20-fold in response to IL-1β or TNF-α, respectively. C3 protein production increases proportionally, reaching levels 36-fold and 18-fold higher than untreated controls upon exposure to IL-1β or TNF-α, respectively. D54-MG cells require a minimal 1 h exposure to IL-1β in order to enhance C3 gene expression significantly, while 4 to 8 h are required for TNF-α. Simultaneous treatment of D54-MG cells with IL-1β and interferon-gamma (IFN-γ) resulted in an additive increase in both C3 mRNA and protein expression, a finding not seen with the combination of TNF-α and IFN-γ. Primary rat astrocytes also express increased C3 mRNA levels after 48 h in response to IL-1β (5.3-fold increase) and TNF-α (7-fold increase), while an additive effect was observed upon simultaneous treatment with both IL-1β and IFN-γ. In the central nervous system (CNS), endogenous complement and cytokine production by astrocytes, and enhancement by IFN-γ, a product of activated T cells often seen in the CNS in neural autoimmune disease, may contribute to the pathogenesis of inflammatory demyelinating diseases such as multiple sclerosis.