Complex response to physiological and drug-induced hepatic heme demand in monoallelic ALAS1 mice

Abstract

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.

The role of the genetic variant FECH rs11660001 in the occurrence of anti‐tuberculosis drug‐induced liver injury

“…Although ALAS1 is the first and rate‐limiting enzyme for haem biosynthesis under normal physiological conditions, 26 two Chinese studies did not observe correlations with susceptibility to AT‐DILI. The results from BALB/c mice carrying a null ALAS1 allele caused by a βGEO insert illustrated the complex response of ALAS1 expression to haem demand but limited evidence that upregulation of a wild‐type allele can compensate for a null allele 27 . Thus, monoallelic ALAS1 mice have a complex response to physiological and drug‐induced hepatic haem demand.…”

“…The results from BALB/c mice carrying a null ALAS1 allele caused by a βGEO insert illustrated the complex response of ALAS1 expression to haem demand but limited evidence that upregulation of a wild-type allele can compensate for a null allele. 27 Thus, monoallelic ALAS1 mice have a complex response to physiological and drug-induced hepatic haem demand. Additionally, as shown by another Chinese study, the occurrence of abnormal porphyrin metabolism is caused by multiple regulatory disorders at the same time, 25 and polymorphisms in ALAS1 might not be sufficient to alter overall enzyme activity.…”