Evidence for Concurrent Effects of Exposure to Environmental Cadmium and Lead on Hepatic CYP2A6 Phenotype and Renal Function Biomarkers in Nonsmokers

Satarug, Soisungwan; Nishijo, Muneko; Ujjin, Pailin; Vanavanitkun, Yuvaree; Baker, Jason

doi:10.1289/ehp.7192

Cited by 29 publications

(15 citation statements)

References 47 publications

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“…A relevant question is whether regulatory similarities between mouse CYP2A5 and human CYP2A6 exist in relation to Nrf2-mediated signaling. Interestingly, a positive correlation between hepatic CYP2A6 activity and environmental cadmium exposure was found in an epidemiological study on a healthy Thai population [34], supporting possible involvement of Nrf2 also in regulation of CYP2A6. In conclusion, our current results suggest that expression of CYP2A5 is modulated by Nrf2 in response to a high fat diet.…”

Section: Discussionmentioning

confidence: 69%

Experimental nonalcoholic fatty liver disease in mice leads to cytochrome p450 2a5 upregulation through nuclear factor erythroid 2-like 2 translocation

Cui

Wang

et al. 2013

Redox Biology

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Mouse cytochrome P450 2A5 (CYP2A5) is upregulated in various liver diseases and a putative common feature for all of these conditions is altered cellular redox status. Nuclear factor erythroid 2-like 2 (Nrf2) is a transcription factor that is post-translationally regulated by oxidative stress and controls the transcription of protective target genes. In the present study, we have characterized the regulation of CYP2A5 by Nrf2 and evaluated gene expression, protein content and activity of anti-oxidant enzymes in the Nrf2+/+ and Nrf2−/− mice model of non-alcoholic fatty liver (NAFLD). After eight weeks of feeding on a high-fat diet, livers from Nrf2−/− mice showed a substantial increase in macro and microvesicular steatosis and a massive increase in the number of neutrophil polymorphs, compared to livers from wild-type mice treated similarly. Livers of Nrf2−/− mice on the high-fat diet exhibited more oxidative stress than their wild-type counterparts as assessed by a significant depletion of reduced glutathione that was coupled with increases in malondialdehyde. Furthermore, results in Nrf2-deficient mice showed that CYP2A5 expression was significantly attenuated in the absence of Nrf2, as was found with the conventional target genes of Nrf2. The treatment of wild-type mice with high-fat diet leaded to nuclear accumulation of Nrf2, and co-immunoprecipitation experiments showed that Nrf2 was bound to Cyp2a5. These findings suggest that the high-fat diet induced alteration in cellular redox status and induction of CYP2A5 was modulated through the redox-sensitive transcription Nrf2.

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Section: Discussionmentioning

confidence: 69%

Experimental nonalcoholic fatty liver disease in mice leads to cytochrome p450 2a5 upregulation through nuclear factor erythroid 2-like 2 translocation

Cui

Wang

et al. 2013

Redox Biology

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“…The average amounts of 7-OHC excreted in the urine in females was higher than that in males, 32,38) while the exposure to cadmium from environmental pollutant and diet resulted in the induction of the enzyme activity. 39) In contrast, plant substances seemed to have a minimal in‰uence on CYP2A6 activity. 40) In addition to those host and W or environmental factors, the intra-genotypic variation of CYP2A6 activity among the subjects may possibly be marked due to the presence of unknown lack-functioned or gain-functioned mutations in the CYP2A6 gene.…”

Section: Discussionmentioning

confidence: 99%

In vivo Evaluation of Coumarin and Nicotine as Probe Drugs to Predict the Metabolic Capacity of CYP2A6 Due to Genetic Polymorphism in Thais

Peamkrasatam

Sriwatanakul

Kiyotani

et al. 2006

Drug Metabolism and Pharmacokinetics

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The association between the distribution characteristics of CYP2A6 catalytic activities toward nicotine and coumarin, and the frequency distribution of CYP2A6 variant alleles reported was estimated in 120 healthy Thais. The distributions of the subjects as classified by the amounts of 7-hydroxycoumarin (7-OHC) excreted in the urine and by cotinine/nicotine ratio in the plasma were clearly bimodal. However, the numbers of apparently poor metabolizers for coumarin and nicotine were different. The inter-individual variability in the in vivo dispositions of coumarin and nicotine closely related to the CYP2A6 genetic polymorphism. There was a close correlation between the rate of 7-OHC excretion in the urine and cotinine/nicotine ratio in the plasma among subjects (R=0.92, p<0.001). The frequency of CYP2A6 allele found in the present study was: CYP2A6*1A=32% (95% CI, 22.1-39.4%), CYP2A6*1B=27% (95% CI, 19.4-33.5%), CYP2A6*9=20% (95% CI, 17.6-23.3%), CYP2A6*4=14% (95% CI, 9.6-17.8%), CYP2A6*7=5% (95% CI, 3.7-9.4%), CYP2A6*10=2% (95% CI, 0.8-5.1%). Subjects having CYP2A6*1A/*1B were found to have a higher rate of 7-OHC excretion, as well as a higher cotinine/nicotine ratio in the plasma compared with those of the other genotypes. In contrast, subjects with CYP2A6*4/*7 and CYP2A6*7/*7 almost lacked any cotinine formation, whereas urinary 7-OHC was still detectable. CYP2A6*9 allele clearly resulted in reduced enzyme activities. Despite the absence of the homozygote for CYP2A6*10 allele, the presence of CYP2A6*10 allele significantly decreased the enzyme activities. The results of the present study demonstrate that in vivo phenotyping of CYP2A6 using nicotine and coumarin are not metabolically equivalent. Nicotine is a better probe according to its specificity, while coumarin is still valuable to be used for a routine CYP2A6 phenotyping since the test employs a non-invasive method.

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“…In addition, HO-1 induction alters expression of certain CYP isoforms. Work in our laboratory indicates cadmium affects liver expression of CYP2C9, CYP4A11, CYP2E1 and CYP2A6 (Baker et al , 2005Satarug et al 2004aSatarug et al ,c, 2006a. CYP2A6 and CYP2E1 are involved in the activation of liver carcinogens.…”

Section: Hypothetical Liver Cell Model Showing Molecular Targets Of Cmentioning

confidence: 86%

Emerging Roles of Cadmium and Heme Oxygenase in Type-2 Diabetes and Cancer Susceptibility

Satarug

2012

Tohoku J. Exp. Med.

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Many decades after an outbreak of severe cadmium poisoning, known as Itai-itai disease, cadmium continues to pose a significant threat to human health worldwide. This review provides an update on the effects of this environmental toxicant cadmium, observed in numerous populations despite modest exposure levels. In addition, it describes the current knowledge on the link between heme catabolism and glycolysis. It examines novel functions of heme oxygenase-2 (HO-2) that protect against type 2-diabetes and obesity, which have emerged from diabetic/obese phenotypes of the HO-2 knockout mouse model. Increased cancer susceptibility in type-2 diabetes has been noted in several large cohorts. This is a cause for concern, given the high prevalence of type-2 diabetes worldwide. A lifetime exposure to cadmium is associated with pre-diabetes, diabetes, and overall cancer mortality with sex-related differences in specific types of cancer. Liver and kidney are target organs for the toxic effects of cadmium. These two organs are central to the maintenance of blood glucose levels. Further, inhibition of gluconeogenesis is a known effect of heme, while cadmium has the propensity to alter heme catabolism. This raises the possibility that cadmium may mimic certain HO-2 deficiency conditions, resulting in diabetic symptoms. Intriguingly, evidence has emerged from a recent study to suggest the potential interaction and co-regulation of HO-2 with the key regulator of glycolysis: 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4). HO-2 could thus be critical to a metabolic switch to cancer-prone cells because the enzyme PFKFB and glycolysis are metabolic requirements for cell proliferation and resistance to apoptosis.

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Evidence for Concurrent Effects of Exposure to Environmental Cadmium and Lead on Hepatic CYP2A6 Phenotype and Renal Function Biomarkers in Nonsmokers

Cited by 29 publications

References 47 publications

Experimental nonalcoholic fatty liver disease in mice leads to cytochrome p450 2a5 upregulation through nuclear factor erythroid 2-like 2 translocation

Experimental nonalcoholic fatty liver disease in mice leads to cytochrome p450 2a5 upregulation through nuclear factor erythroid 2-like 2 translocation

In vivo Evaluation of Coumarin and Nicotine as Probe Drugs to Predict the Metabolic Capacity of CYP2A6 Due to Genetic Polymorphism in Thais

Emerging Roles of Cadmium and Heme Oxygenase in Type-2 Diabetes and Cancer Susceptibility

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