The Non-Linear Child: Ontogeny, Isoniazid Concentration, and NAT2 Genotype Modulate Enzyme Reaction Kinetics and Metabolism

Zoe Rogers, Hiwot Hiruy, Jotam G. Pasipanodya, Chris Mbowane, John Adamson, Lihle Ngotho, Farina Karim, Prakash Jeena, William Bishai, Tawanda Gumbo

Research output: Contribution to journalArticlepeer-review

Abstract

N-acetyltransferase 2 (NAT2) catalyzes the acetylation of isoniazid to N-acetylisoniazid. NAT2 polymorphism explains 88% of isoniazid clearance variability in adults. We examined the effects of clinical and genetic factors on Michaelis-Menten reaction kinetic constants of maximum velocity (Vmax) and affinity (Km) in children 0–10 years old. We measured the rates of isoniazid elimination and N-acetylisoniazid production in the blood of 30 children. Since maturation effects could be non-linear, we utilized a pharmacometric approach and the artificial intelligence method, multivariate adaptive regression splines (MARS), to identify factors predicting NAT2 Vmax and Km by examining clinical, genetic, and laboratory factors in toto. Isoniazid concentration predicted both Vmax and Km and superseded the contribution of NAT2 genotype. Age non-linearly modified the NAT2 genotype contribution until maturation at ≥ 5.3 years. Thus, enzyme efficiency was constrained by substrate concentration, genes, and age. Since MARS output is in the form of basis functions and equations, it allows multiscale systems modeling from the level of cellular chemical reactions to whole body physiological parameters, by automatic selection of significant predictors by the algorithm.

Original languageEnglish (US)
Pages (from-to)118-126
Number of pages9
JournalEBioMedicine
Volume11
DOIs
StatePublished - Sep 1 2016

Keywords

  • Artificial intelligence
  • Isoniazid concentration
  • Maturation
  • NAT2 genotype
  • NAT2 reaction kinetics

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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