Firstly the causes of liver failure in those taking the drug (1):
The cause of liver injury due to Isoniazid is believed to be
accumulation of a toxic intermediate of its metabolism. Rates of
injury may be somewhat higher in patients with a slow acetylation
status, marked by genotypic variants in N-acetylation, or with
abnormalities in CYP 2E1, the second major enzymatic pathway of its
metabolism. [..] Despite the lack of prominent features of
hypersensitivity, rapid recurrence of injury can occur with
rechallenge, suggesting that the injury is immune-mediated, at least
- The CYP 2E1 referred to is thought to be responsible for clearing the body of drugs and toxins:
Human CYP2E1 catalyses the metabolism of low-molecular-weight
xenobiotics, including drugs [..], solvents [..] and procarcinogens
There are many known versions of this, the prevalence of some is known to vary by race (3):
Both rs3813867:C and rs2031920:T alleles are common in Asian
populations but rare in Caucasians and Africans (Zavras et al., 2002).
But no detailed research of the link between specific CYP2E1 variants present and liver toxicity to Isoniazid in African subjects.
- Genotypic variants in N-acetylation (2).
This refers to a group of alleles that are thought to be involved in the production of enzymes or other substances which render environmental substances (typically plant or bacterial toxins and the like) harmless, and reduce their carcinogenicity. There are in excess of 14 known variants of this, and the number of variants in African-heritage peoples is typically larger than that found in Caucasian subjects. The implication being that the greater diversity in this part of the genome confers a disadvantage in breaking-down Isoniazid, as a narrow set of variants, which are found more frequently in Caucasians is more effective in rendering it non-noxious.
There are indicators that more than one variation in the phenotypes which are more common in Africans may well result in lower tolerance to the toxic effects of this drug or its metabolites, however the research has yet to definitively predict which variants will be at risk especially as it seems to be potentially more than one factor at play including an immune-mediated response.
(1) LiverTox: Clinical and Research Information on Drug-Induced Liver Injury National Library of Medicine.
(2) Differences in N-acetylation genotypes between Caucasians and BlackSouth Africans: implications for cancer prevention Researchgate.