title: The Non-Linear Child: Ontogeny, Isoniazid Concentration, and NAT2 Genotype Modulate Enzyme Reaction Kinetics and Metabolism.
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 0-10years 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 Vmaxand Kmby examining clinical, genetic, and laboratory factors in toto. Isoniazid concentration predicted both Vmaxand Kmand superseded the contribution of NAT2 genotype. Age non-linearly modified the NAT2 genotype contribution until maturation at ≥5.3years. 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.
authors.affiliation: KwaZulu-Natal Research Institute for TB and HIV, Durban 4001, South Africa.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Rogers
authors.affiliation: Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA.
authors.forename: Hiwot
authors.initials: H
authors.lastname: Hiruy
authors.affiliation: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX 75204, USA.
authors.forename: Jotam G
authors.initials: JG
authors.lastname: Pasipanodya
authors.affiliation: Dept of Pediatrics, Nelson Mandela School of Medicine, UKZN, Durban 4001, South Africa.
authors.forename: Chris
authors.initials: C
authors.lastname: Mbowane
authors.affiliation: KwaZulu-Natal Research Institute for TB and HIV, Durban 4001, South Africa.
authors.forename: John
authors.initials: J
authors.lastname: Adamson
authors.affiliation: KwaZulu-Natal Research Institute for TB and HIV, Durban 4001, South Africa.
authors.forename: Lihle
authors.initials: L
authors.lastname: Ngotho
authors.affiliation: KwaZulu-Natal Research Institute for TB and HIV, Durban 4001, South Africa.
authors.forename: Farina
authors.initials: F
authors.lastname: Karim
authors.affiliation: Dept of Pediatrics, Nelson Mandela School of Medicine, UKZN, Durban 4001, South Africa.
authors.forename: Prakash
authors.initials: P
authors.lastname: Jeena
authors.affiliation: Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
authors.forename: William
authors.initials: W
authors.lastname: Bishai
authors.affiliation: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX 75204, USA; Department of Medicine, University of Cape Town, Observatory, South Africa. Electronic address: tawanda.gumbo@baylorhealth.edu.
authors.forename: Tawanda
authors.initials: T
authors.lastname: Gumbo
mesh_terms: D000483:Alleles; D000995:Antitubercular Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001191:Arylamine N-Acetyltransferase / Q000235:genetics* / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D004789:Enzyme Activation / Q000187:drug effects; D005838:Genotype; D006801:Humans; D007223:Infant; D007538:Isoniazid / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007700:Kinetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D014376:Tuberculosis / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism
chemical_list: D000995:Antitubercular Agents; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D007538:Isoniazid
keywords: Artificial intelligence; Isoniazid concentration; Maturation; NAT2 genotype; NAT2 reaction kinetics