TY - JOUR
T1 - The Non-Linear Child
T2 - Ontogeny, Isoniazid Concentration, and NAT2 Genotype Modulate Enzyme Reaction Kinetics and Metabolism
AU - Rogers, Zoe
AU - Hiruy, Hiwot
AU - Pasipanodya, Jotam G.
AU - Mbowane, Chris
AU - Adamson, John
AU - Ngotho, Lihle
AU - Karim, Farina
AU - Jeena, Prakash
AU - Bishai, William
AU - Gumbo, Tawanda
N1 - Funding Information:
The support of the Howard Hughes Medical Institute and NIH grants AI37856 , AI36973 , 97138 , R56AI111985 is gratefully acknowledged.
Publisher Copyright:
© 2016 Forschungsgesellschaft für Arbeitsphysiologie und Arbeitschutz e.V.
PY - 2016/9/1
Y1 - 2016/9/1
N2 - 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 Isoniazid concentration predicted both Vmax and Km and superseded the contribution of NAT2 genotype.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.
AB - 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.
KW - Artificial intelligence
KW - Isoniazid concentration
KW - Maturation
KW - NAT2 genotype
KW - NAT2 reaction kinetics
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U2 - 10.1016/j.ebiom.2016.07.031
DO - 10.1016/j.ebiom.2016.07.031
M3 - Article
C2 - 27528266
AN - SCOPUS:84994877198
SN - 2352-3964
VL - 11
SP - 118
EP - 126
JO - EBioMedicine
JF - EBioMedicine
ER -