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Development of oxidative stress by cytochrome P450 induction in rodents is selective for barbiturates and related to loss of pyridine nucleotide-dependent protective systems.
J Biol Chem. 2008 Jun 20; 283(25):17147-57
Paul Hollenberg, University of Michigan, MI, USA. F1000 Pharmacology & Drug Discovery
22 Sep 2008 | New Finding
This article provides an explanation for the discrepancy between studies on oxidative stress done in vitro and in vivo.
The formation of reactive oxygen species (ROS) ultimately leading to oxidative stress has long been considered to play an important role in many types of toxicity and the metabolism of toxicants by the microsomal cytochrome P450s has been suggested to be a major source of ROS.
P450 induction by agents such as phenobarbital, beta-naphthoflavone, or clofibrate was thought to increase toxicity by increasing the production of ROS during the metabolism of various toxicants and thereby result in increased oxidative stress and subsequent toxicity. The studies described here provide strong evidence that the inducing agents may also work by attenuating the levels of protective systems such as nicotinamide N-methyltransferase, glutathione peroxidase, and glutathione reductase, all of which play important roles in protecting against oxidative stress. The authors suggest that the down-regulation of these protective systems may be more important in oxidative stress than the induction of the P450s. They also point out that in vivo models may be much more relevant for studying oxidative stress since isolated systems and cultured cells may lack some of these protective systems or they may be regulated in different ways from in vivo.
Competing interests: None declared
Hollenberg P: "This article provides an explanation for the discrepancy between studies on oxidative stress done in..." Evaluation of: [Dostalek M et al. Development of oxidative stress by cytochrome P450 induction in rodents is selective for barbiturates and related to loss of pyridine nucleotide-dependent protective systems. J Biol Chem. 2008 Jun 20; 283(25):17147-57; doi: 10.1074/jbc.M802447200]. Faculty of 1000, 22 Sep 2008. F1000.com/1122801#eval579887
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Hollenberg P: 2008. F1000.com/1122801#eval579887
Faculty of 1000 evaluations, dissents and comments for [Dostalek M et al. Development of oxidative stress by cytochrome P450 induction in rodents is selective for barbiturates and related to loss of pyridine nucleotide-dependent protective systems. J Biol Chem. 2008 Jun 20; 283(25):17147-57; doi: 10.1074/jbc.M802447200]. Faculty of 1000, 22 Sep 2008. F1000.com/1122801
Short form
Faculty of 1000: 2008. F1000.com/1122801
Reactive oxygen species (ROS) and oxidative stress have been considered in a variety of disease models, and cytochrome P450 (P450) enzymes have been suggested to be a source of ROS. Induction of P450s by phenobarbital (PB), beta-naphthoflavone (betaNF), or clofibrate in a mouse model increased ROS parameters in the isolated liver microsomes, but isoniazid treatment did not. However, when F(2)-isoprostanes (F(2)-IsoPs) were measured in tissues and urine, PB showed the strongest effect and betaNF had a measurable but weaker effect. The same trend was seen when an Nfr2-based transgene reporter sensitive to ROS was analyzed in the mice. This pattern had been seen earlier with F(2)-IsoPs both in vitro and in vivo with rats (Dostalek, M., Brooks, J. D., Hardy, K. D., Milne, G. L., Moore, M. M., Sharma, S., Morrow, J. D., and Guengerich, F. P. (2007) Mol. Pharmacol. 72, 1419-1424). One possibility for the general in vitro-in vivo discrepancy in oxidative stress found in both mice and rats is that PB treatment might attenuate protective systems. One potential candidate suggested by an mRNA microarray was nicotinamide N-methyltransferase. PB was found to elevate nicotinamide N-methyltransferase activity 3- to 4-fold in mice and rats and to attenuate levels of NAD(+), NADP(+), NADH, and NADPH in both species (20-40%), due to the enhanced excretion of (N-methyl)nicotinamide. PB also down-regulated glutathione peroxidase and glutathione reductase, which together constitute a key enzymatic system that uses NADPH in protecting against oxidative stress. These multiple effects on the protective systems are proposed to be more important than P450 induction in oxidative stress and emphasize the importance of studying in vivo models.
DOI: 10.1074/jbc.M802447200
PMID: 18442974
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