Role of cytochrome P450 in the induction of pathological conditions

Main Article Content

Nadta Sukkasem
Kanokwan Jarukamjorn


Cytochrome P450s (CYP450s) are a superfamily of enzymes responsible for metabolism of various chemicals, producing intermediates as reactive oxygen species (ROS) during the process. Accumulation of ROS in cells and tissues alters the balance between oxidants and anti-oxidants in the cells, resulting in oxidative stress which causes pathology in body according to where it occurs. CYP450s are comprised of numerous isoforms. Each isoform play a role in metabolism of different chemicals. Hence, induction of different CYP450 isoforms results in different pathologic diseases. For example, CYP2C induction results in vascular damage via production of leukotoxin and oxynitrate free radicals. Induction of CYP2E leads to hepatic, central nervous system, and cardiac damage, and breast cancer from induction of ROS production. Induction of CYP2D causes damage of central nervous system due to alteration of neurotransmitter metabolisms. Induction of CYP3A results in oxidative stress in liver and hepatotoxicity. Induction of CYP4A damages renal arteries, and then results in renal ischemia. Therefore, consumption of chemicals, including drugs, foods, herbs, or toxicants, which can induce CYP450 enzymes may lead to pathologic conditions via induction of oxidative stress from activation of CYP450s.


Download data is not yet available.

Article Details

Review Article


Arifi MN, Maayah ZH, Alshamrani AA, Korashy HM. Impact of cigarette smoke exposure on the expression of cardiac hypertrophic genes, cytochrome P450 enzymes, and oxidative stress markers in rats. J Toxicol Sci 2012; 37(5): 1083-1090.

Bellamine A, Wang Y, Waterman MR, et al. Characterization of the CYP4A11 gene, a second CYP4A gene in humans. Arch Biochem Biophys 2003; 409: 221-227.

Cederbaum AI, Wu D, Mari M, Bai J. CYP2E1-dependent toxicity and oxidative stress in HEPG2 cells. Free RadicBiol Med 2001; 31(12): 1539-1543.

Chaudhary KR, Batchu SN, Seubert JM. Cytochrome P450 enzymes and the heart. Life Sci 2009; 61(10): 954-960.

Cheng J, Ma X, Krausz KW, Idle JR, Gonzalez FJ. Rifampicin-activated human pregnane X receptor and CYP3A4 induction enhance acetaminophen-induced toxicity. Drug Metab Dispos 2009; 37: 1611-1621.

Cui JY, Renaud HJ, Klaassen CD. Ontogeny of novel cytochrome P450 gene isoforms during postnatal liver maturation in mice. Drug Metab Dispos 2012; 40(6): 1226-1237.

Durackova Z. Some current insights into oxidative stress. Physiol Res 2010; 59: 459-469.

Eid AA, Gorin Y, Fag BM, et al. Mechanisms of podocyte Injury in diabetes role of cytochrome P450 and NADPH oxidases. Diabetes 2009; 58: 1201-1211.

Fichtlscherer S, Dimmeler S, Breuer S, Busse R, Zeiher AM, Fleming I. Inhibition of cytochrome P450 2C9 improves endothelium-dependent, nitric oxide-mediated vasodilatation in patients with coronary artery disease. Circulation 2004; 109: 178-183.

Flachsbart F, Ufer M, Kleindorp R, Nikolaus S, Schreiber S, Nebel A. Genetic Variation in the CYP2C Monooxygenase enzyme subfamily shows no association with longevity in a German population. J Gerontol A BiolSci Med Sci 2011; 66A(11) : 1186-1191.

Fleming I. Cytochrome P450 Enzymes in vascular homeostasis. Circ Res 2001; 89: 753-762.

Hasler JA, Estabrook R, Murray M,et al. Human cytochromes P450. Mol Aspects Med 1999; 20: 1-137.

Hunter AL, Bai N, Laher I, Granville DJ. Cytochrome p450 2C inhibition reduces post-ischemic vascular dysfunction. Vascul Pharmacol 2005; 43: 213-219.

Imig JD. Epoxides and soluble epoxide hydrolase in cardiovascular physiology. Physiol Rev 2012; 92(1): 101-130.

Jin M, Ande A, Kumar A, Kumar S. Regulation of cytochrome P450 2e1 expression by ethanol: role of oxidative stress-mediated pkc/jnk/sp1 pathway. Cell Death Dis 2013; 21(4): e554-563.

Leung T, Rajendran R, Singh S, Garva R, Demonacos MK, DemonacosC. Cytochrome P450 2E1 (CYP2E1) regulates the response to oxidative stress and migration of breast cancer cells. Breast Cancer Res 2013; 15(6): R107-118.

Lewis DF. Oxidative stress: the role of cytochromes P450 in oxygen activation. J Chem Technol Biotechnol 2002; 77: 1095-1100.

Lu D, Ma Y, Zhang W, et al. Knockdown of cytochrome P450 2E1 inhibits oxidative stress and apoptosis in the cTnTR141W dilated cardiomyopathy Transgenic Mice. Hypertension 2012; 60: 81-89.

Lu Y, Cederbaum AI. CYP2E1 and oxidative liver injury by alcohol. ‎Free Radic Biol Med 2008; 44: 723-738.

Lukaszewicz KM, Lombard JH. Role of the CYP4A/20-HETE pathway in vascular dysfunction of the Dahl salt-sensitive rat. Clin Sci 2013; 124(12) : 695-700.

Makia NL, Surapureddi S, Monostory K, Prough RA, Goldstein JA. Regulation of human CYP2C9 expression by electrophilic stress involves activator protein 1 activation and DNA looping. Mol Pharmacol 2014; 86: 125-137.

Martignoni M, Groothuis GM, Kanter R. Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction. Expert Opin Drug MetabToxicol 2006; 2(6): 875-894.

Miksys SL, Tyndale RF. Drug-metabolizing cytochrome P450s in the brain. J Psychiatry Neurosci 2002; 27(6): 406-415.

Minamiya Y, Takemura S, Toyokuni S, et al. CYP3A induction aggravates endotoxemic liver injury via reactive oxygen species in male rats. Free Radic Biol Med 2004; 37(5): 703-712.

Peng HM, Coon MJ. Regulation of rabbit cytochrome P450 2E1 expression in HepG2 cells by insulin and thyroid hormone. Mol Pharmacol 1998; 54: 740-747.

Puntarulo S, Cederbaum AI. Production of reactive oxygen species by microsomes enriched in specific human cytochrome P450 enzymes. Free Radic Biol Med 1998; 24: 1324-1330.

Qi XM, Miao LL, Cai Y, Gong LK, Ren J. ROS generated by CYP450, especially CYP2E1, mediate mitochondrial dysfunction induced by tetrandrine in rat hepatocytes. Acta Pharmacol Sin 2013; 34: 1229-1236.

Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB. Oxidative stress, inflammation, and cancer: How are they linked?. Free Radic Biol Med 2010; 49: 1603-1616.

Thompson CM, Capdevila JH, Strobel HW. Recombinant cytochrome P450 2D18 metabolism of dopamine and arachidonic Acid. J Pharmacol Exp Ther 2000; 294: 1120-1130.

Toth P, Rozsa B, Springo Z, Doczi T, Koller A. Isolated human and rat cerebral arteries constrict to increases in flow: role of 20-HETE and TP receptors. J Cereb Blood Flow Metab 2011; 31: 2096-2105.

Uzbay IT, Usanmaz SE, Akarsu ES.Effects of chronic ethanol administration on serotonin metabolism in the various regions of the rat brain. Neurochem Res 2000; 25: 257-262.

Viswanathan S, Hammock BD, Newman JW, Meerarani P, Toborek M, Hennig B. Involvement of CYP 2C9 in mediating the proinflammatory effects of linoleic acid in vascular endothelial cells. J Am Coll Nutr 2013; 22(6): 502-510.

Ward NC, Puddey IB, Hodgson JM, Beilin LJ, Croft KD. Urinary 20-hydroxyeicosatetraenoic acid excretion is associated with oxidative stress in hypertensive subjects. ‎Free Radic Biol Med 2005; 38: 1032-1036.

Weltman MD, Farrel GC, Hall P, Sundberg MI, Liddle C. Hepatic cytochrome P450 2E1 is increased in patients with nonalcoholic steatohepatitis. Hepatology 1998; 27(1): 128-133.

Woodcroft KJ, Hafner MS, Novak RF. Insulin signaling in the transcriptional and posttranscriptional regulation of CYP2E1 expression. Hepatology2002; 35 (2): 263-273.

Wu D, Cederbaum AI. Oxidative stress mediated toxicity exerted by ethanol-inducible CYP2E1. Toxicol Appl Pharm 2005; 207: S70-S76.

Zangar RC, Davydov DR, Verma S. Mechanisms that regulate production of reactive oxygen species by cytochrome P450. Toxicol Appl Pharm 2004; 199: 316-331.

Zimatkin SM, Pronko SP, Vasiliou V, Gonzalez FJ, Deitrich RA. Enzymatic mechanisms of ethanol oxidation in the brain. Alcohol Clin Exp Res 2006; 30(9): 1500-1505.