Regulation of 5-aminolevulinate synthase 1 (ALAS1) for nonerythroid heme is critical for respiration, cell signaling mechanisms and steroid/drug metabolism. ALAS1 is induced in some genetic disorders but unlike other genes in the heme pathway, a gene variant of ALAS1 associated with inherited disease has not been reported. BALB/c mice carrying a null ALAS1 allele caused by a βGEO insert were developed and used to determine the consequences of heme demand of a semi gene copy number. Homozygous disruption of ALAS1 (−/−) was lethal for embryo development post day 6.5 but expression in heterozygotes (+/−) was sufficient for the number of offspring and survival. In both wild type (WT +/+) and +/− mice expression of ALAS1 RNA was greatest in liver and harderian gland and much lower in kidney, lung, heart, brain and spleen. The effects of one WT ALAS1 allele in +/− mice on mRNA levels in liver and harderian gland were less marked compared to brain and other organs that were examined. Many other genes were up-regulated by heterozygosity in liver and brain but to a minimal extent. Hepatic heme oxygenase 1 (HMOX1) mRNA expression was significantly lower in +/− mice but not in brain. No elevated translation of WT allele ALAS1 mRNA was detected in +/− liver as a compensatory mechanism for the disabled allele. Fasting induced ALAS1 mRNA in both WT and +/− mice but only in +/− was this manifest as increased ALAS1 protein. The hepatic protoporphyria-inducing drug 4-ethyl-DDC caused induction of hepatic ALAS1 mRNA and protein levels in both WT and +/− mice but markedly less in the mice with only one intact allele. The findings illustrate the complex response of ALAS1 expression for heme demand but limited evidence that upregulation of a wild type allele can compensate for a null allele.
Adverse drug reactions are often idiosyncratic responses to administered medicines or herbal remedies that may be the consequence of multiple interactions between physiological and genetic factors with drug target and off-target effects. Identification and resolution of the mechanisms of these factors for individuals can prove problematic. Genetic variants or acquired fluctuations in the activity of the haem metabolism enzymes are well established predisposition factors in some known clinical hepatic disorders.Some of these disorders of nonerythroid haem supply can be triggered by drugs, hormones and other agents that normally have no untoward effects. Thus these mutations affecting the activity of the enzymes in the haem pathway can be regarded as predisposing genetic factors causing adverse reactions of some drugs in susceptible individuals. Carriers may be non-symptomatic for a prolonged period until the combination of factors such as consumption of medicinal products, alcohol, stress, hormone fluctuations and change in dietary habits trigger clinical symptoms. Despite these inherited or acquired changes of the haem metabolic pathway, many carriers do not develop symptoms illustrating the involvement of other unknown genetic components. In addition, haem is of fundamental cellular importance not only for respiratory cytochromes and oxygen transport but for many other roles such as for cytochrome P450, NO signalling, and microRNA formation. For these reasons, nonerythroid haem synthesis is under complex transcriptional and translational regulation linked to age, nutrition and circadian rhythm and to hormonal, drug and stress responses. Besides those already known, interference and genetic differences in the flux of supply, recruitment and use of haem for such fundamental processes may contribute to adverse drug reactions in metabolic arenas that are not yet recognised.
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