The Ontogeny and Population Variability of Human Hepatic NADPH Dehydrogenase Quinone Oxido-Reductase 1 (NQO1)

Abstract

The NADPH dehydrogenase quinone oxido-reductase 1 (NQO1) enzyme is an antioxidant and metabolic enzyme that performs two electron reduction of quinones and other chemicals. Based on the physiologic role(s) of NQO1, we hypothesized that expression and activity of this enzyme would vary with age and other demographic variables. Cytosols from 117 archived human livers were investigated for changes in NQO1 with age, sex, obesity, and ethnicity. Protein expression but not activity of NQO1 was weakly negatively correlated with age (Spearman r = -0.2, P = 0.03). No sex differences were observed for either protein expression or activity and for ethnicity; Caucasians had greater NQO1 activity than Asians (P < 0.05). Overweight children had statistically significantly higher NQO1 activity as compared with ideal weight children (P < 0.05) although this difference was not observed in adults. These findings establish that NQO1 is approximately as active in children as adults. However, modeled NQO1 clearance (both allometric and physiologically based pharmacokinetics) predicted maturation at 23 to 26 years. This is almost certainly an overestimate, with error in the model resulting from a small sample size and inability to scale for age-related changes in hepatic cellularity and/or cytosolic protein content, and indicates a delay in reaching maximum clearance through the NQO1 pathway that is affected by physiologic development as much, or more than, biochemical development. Obesity may increase hepatic NQO1 activity in children, which is likely a protective mechanism in oxidative stress, but may also have significant implications for drug and chemical disposition in obese children.

The ontogeny and population variability of human hepatic dihydronicotinamide riboside:quinone oxidoreductase (NQO2)

“…Hepatic blood flow ( Q hepatic ) of 90 L/h, an average adult liver size of 1500 g and the cytosolic protein scaling parameter of 80.7 mg/g of liver were used. The unbound fraction of DCPIP in the incubation (fu inc ) was 0.595 as previously determined by us with the same level of protein and buffers used herein . To scale for hepatic clearance in children, both allometry and physiologically based pharmacokinetic (PBPK) analyses were used.…”

“…To scale for hepatic clearance in children, both allometry and physiologically based pharmacokinetic (PBPK) analyses were used. The allometric and PBPK models used to predict CL pediatric are exactly as described in our previous paper …”

“…For example, in the adult human liver NQO1 and NQO2 mRNA are differentially regulated and expressed in both normal and tumoral tissues . Also with respect to studying NQO family proteins in the human liver, we have recently characterized the ontogeny and population variability of NQO1 . Although NQO1 biochemical activities are as high in neonates and children as in adults, hepatic clearance of substrates through the NQO1 pathway takes up to mid‐20s to develop, due to a combination of biochemical and physiological maturation.…”

“…Although NQO1 biochemical activities are as high in neonates and children as in adults, hepatic clearance of substrates through the NQO1 pathway takes up to mid‐20s to develop, due to a combination of biochemical and physiological maturation. Moreover, up to 15% of the population showed extremely high levels of NQO1 activity independent of genetic polymorphisms, ascribed to environmental upregulation . With the previous study in mind, and because hepatic NQO1 and NQO2 are differentially regulated, the objective of this study was to determine the ontogeny and population variability in NQO2 enzymes and their contribution to hepatic clearance.…”

Tetrahydroxystilbene Glucoside Exerts Cytoprotective Effect against Hydrogen Peroxide-induced Cell Death Involving ROS Production and Antioxidant Enzyme Activation

“…Indeed, ample evidence currently supports the notion that HO-1 serves to provide potent cytoprotective effects in many in vitro and in vivo models of oxidantinduced cellular and tissue injury. The NADPHquinone oxidoreductase 1 (NQO1) is a predominantly cytosolic enzyme which provides cells with multiple layers of protection against oxidative stress, including the direct detoxification of highly reactive quinones [6,7] . *Address for correspondence E-mail: zhj@zcmu.edu.cn…”