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.
Footnotes
- Received December 1, 2015.
- Accepted February 5, 2016.
These studies were supported by the Hawaii Biorepository, which is funded by the National Institutes of Health National Institute on Minority Health and Health Disparities [Grant MD007601].
- Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|