Treatment of many inherited liver enzyme deficiencies muscle. These mice exhibited hyperphenylalaninemia at requires the removal of toxic intermediate metabolites frombaseline, but serum phenylalanine levels decreased sigthe blood of affected individuals. We propose that circulatnificantly when the mice were supplemented with tetrahyding toxins can be adequately cleared and disease phenorobiopterin (BH 4 ), a required cofactor for PAH. This is the type influenced by enzyme expressed in tissues other than first demonstration that a liver-specific enzyme, when the liver. Phenylalanine hydroxylase (PAH) activity was expressed in a heterologous tissue and supplied with constitutively expressed in skeletal and cardiac muscle of necessary cofactors, can effectively clear toxic metabolites transgenic mice which carried the PAH cDNA under the from the circulation of individuals with inherited enzyme transcriptional control of the mouse muscle creatine kinase deficiency. This result suggests that gene therapy targeted promoter. Muscle PAH-expressing mice were bred to liver to heterologous tissues, such as muscle, will be effective PAH-deficient, hyperphenylalaninemic mice to yield proin the treatment of selected inborn errors of metabolism. geny that lack PAH activity in liver but express PAH in
Ewes bearing twins were starved for 10 days during the last month of gestation to induce ovine pregnancy toxaemia (OPT). Glucose turnover was measl,lred by a primed continuous infusion of [U_ '4C]_ and [6-3 HJglucose at the end of 10 days of starvation (non-susceptible), or earlier when ewes became recumbent with OPT (susceptible). All ewes were slaughtered at the end of the infusion and hepatocytes were prepared in order to measure glucose production from different substrates. Many of the ewes had dead foetuses when slaughtered. Glucose production rates by hepatocytes with the substrates propionate, lactate or alanine were significantly less from the susceptible ewes than were those from non-susceptible ewes. These low rates were not stimulated by incubation with glucagon (10-8 M), glutamine or glycerol. Rates of glucose turnover and of hepatic glucose production from all substrates were higher for ewes with dead than with live foetuses. The data support the hypothesis that pathogenesis of OPT is related to an impairment of hepatic gluconeogenesis, and further suggest that, in starved pregnant ewes, maternal glucose production may be restrained in the presence of a live foetus.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.