Perilla frutescens modulates CYP1A1/2 and HO-1 and activates Nrf2 in oxidative stress-induced hepatotoxicity

Jeong Han Kang, Sung Yong Yang, Jaeho Ha, Kwang Won Lee

Research output: Contribution to journalArticle

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Abstract

We speculated that lipid peroxidation induced by tert-butyl hydroperoxide (t-BHP) in liver is closely linked with the metabolism mediated by CYPs. In this study, we have examined the effect of Perilla leaf extract (PLE) on CYPs using 7-ethoxyresorufin-O-deethylase (EROD, indicator of CYP1A1), 7-methoxyresorufin-O-demethylase (MROD, indicator of CYP1A2), erythromycin N-demethylase (ERDM, indicator of CYP3A), and p-nitrophenol hydroxylase (PNPH, indicator of CYP2E1) in rat liver. Rats orally pretreated with PLE (250, 500, and 1,000 mg/kg b.w.) for 5 days were administered with a single i.p. dose of t-BHP (0.5 mmol/kg). Kinetic analysis of CYP1A1/2 activities in t-BHP-treated liver demonstrated that PLE inhibits the enzyme activities by competitive and noncompetitive inhibitions. The pretreatment with PLE decreased the expression of CYP1A1/2 mRNA and protein compared with t-BHP treatment alone. A Phase II enzyme, heme oxygenase-1 (HO-1), is involved in hepatoprotection against oxidative damage, and we confirmed that PLE increases the levels of HO-1 mRNA and protein, as well as its activity in t-BHP-induced liver damage. PLE administration resulted in enhanced nuclear translocation and ARE binding of NF-E2-related factor 2. These findings suggest that PLE protects against t-BHP-induced hepatotoxicity through modulated activity and expression of selective CYPs, and ARE-driven induction of HO-1 expression and its activity.

Original languageEnglish
Pages (from-to)305-315
Number of pages11
JournalJournal of the Korean Society for Applied Biological Chemistry
Volume58
Issue number3
DOIs
Publication statusPublished - 2015 Jun 1

Fingerprint

Perilla frutescens
Perilla
tert-Butylhydroperoxide
Cytochrome P-450 CYP1A1
Heme Oxygenase-1
Oxidative stress
Oxidative Stress
Liver
Cytochrome P-450 CYP3A
Rats
NF-E2-Related Factor 2
Cholesterol 7-alpha-Hydroxylase
Enzyme inhibition
Cytochrome P-450 CYP2E1
Cytochrome P-450 CYP1A2
Messenger RNA
Enzyme activity
Mixed Function Oxygenases
Metabolism
Enzymes

Keywords

  • Cytochrome P450s
  • Hepatoprotection
  • HO-1
  • Nrf2
  • Oxidative stress
  • Perilla frutescens

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Organic Chemistry

Cite this

Perilla frutescens modulates CYP1A1/2 and HO-1 and activates Nrf2 in oxidative stress-induced hepatotoxicity. / Kang, Jeong Han; Yang, Sung Yong; Ha, Jaeho; Lee, Kwang Won.

In: Journal of the Korean Society for Applied Biological Chemistry, Vol. 58, No. 3, 01.06.2015, p. 305-315.

Research output: Contribution to journalArticle

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abstract = "We speculated that lipid peroxidation induced by tert-butyl hydroperoxide (t-BHP) in liver is closely linked with the metabolism mediated by CYPs. In this study, we have examined the effect of Perilla leaf extract (PLE) on CYPs using 7-ethoxyresorufin-O-deethylase (EROD, indicator of CYP1A1), 7-methoxyresorufin-O-demethylase (MROD, indicator of CYP1A2), erythromycin N-demethylase (ERDM, indicator of CYP3A), and p-nitrophenol hydroxylase (PNPH, indicator of CYP2E1) in rat liver. Rats orally pretreated with PLE (250, 500, and 1,000 mg/kg b.w.) for 5 days were administered with a single i.p. dose of t-BHP (0.5 mmol/kg). Kinetic analysis of CYP1A1/2 activities in t-BHP-treated liver demonstrated that PLE inhibits the enzyme activities by competitive and noncompetitive inhibitions. The pretreatment with PLE decreased the expression of CYP1A1/2 mRNA and protein compared with t-BHP treatment alone. A Phase II enzyme, heme oxygenase-1 (HO-1), is involved in hepatoprotection against oxidative damage, and we confirmed that PLE increases the levels of HO-1 mRNA and protein, as well as its activity in t-BHP-induced liver damage. PLE administration resulted in enhanced nuclear translocation and ARE binding of NF-E2-related factor 2. These findings suggest that PLE protects against t-BHP-induced hepatotoxicity through modulated activity and expression of selective CYPs, and ARE-driven induction of HO-1 expression and its activity.",
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AB - We speculated that lipid peroxidation induced by tert-butyl hydroperoxide (t-BHP) in liver is closely linked with the metabolism mediated by CYPs. In this study, we have examined the effect of Perilla leaf extract (PLE) on CYPs using 7-ethoxyresorufin-O-deethylase (EROD, indicator of CYP1A1), 7-methoxyresorufin-O-demethylase (MROD, indicator of CYP1A2), erythromycin N-demethylase (ERDM, indicator of CYP3A), and p-nitrophenol hydroxylase (PNPH, indicator of CYP2E1) in rat liver. Rats orally pretreated with PLE (250, 500, and 1,000 mg/kg b.w.) for 5 days were administered with a single i.p. dose of t-BHP (0.5 mmol/kg). Kinetic analysis of CYP1A1/2 activities in t-BHP-treated liver demonstrated that PLE inhibits the enzyme activities by competitive and noncompetitive inhibitions. The pretreatment with PLE decreased the expression of CYP1A1/2 mRNA and protein compared with t-BHP treatment alone. A Phase II enzyme, heme oxygenase-1 (HO-1), is involved in hepatoprotection against oxidative damage, and we confirmed that PLE increases the levels of HO-1 mRNA and protein, as well as its activity in t-BHP-induced liver damage. PLE administration resulted in enhanced nuclear translocation and ARE binding of NF-E2-related factor 2. These findings suggest that PLE protects against t-BHP-induced hepatotoxicity through modulated activity and expression of selective CYPs, and ARE-driven induction of HO-1 expression and its activity.

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KW - HO-1

KW - Nrf2

KW - Oxidative stress

KW - Perilla frutescens

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