RGD Reference Report - Cooperation of the inducible nitric oxide synthase and cytochrome P450 1A1 in mediating lung inflammation and mutagenicity induced by diesel exhaust particles. - Rat Genome Database

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Cooperation of the inducible nitric oxide synthase and cytochrome P450 1A1 in mediating lung inflammation and mutagenicity induced by diesel exhaust particles.

Authors: Zhao, H  Barger, MW  Ma, JK  Castranova, V  Ma, JY 
Citation: Zhao H, etal., Environ Health Perspect. 2006 Aug;114(8):1253-8.
RGD ID: 5147744
Pubmed: PMID:16882535   (View Abstract at PubMed)
PMCID: PMC1552032   (View Article at PubMed Central)

Diesel exhaust particles (DEPs) have been shown to activate oxidant generation by alveolar macrophages (AMs), alter xenobiotic metabolic pathways, and modify the balance of pro-antiinflammatory cytokines. In this study we investigated the role of nitric oxide (NO) in DEP-mediated and DEP organic extract (DEPE) -mediated inflammatory responses and evaluated the interaction of inducible NO synthase (iNOS) and cytochrome P450 1A1 (CYP1A1). Male Sprague-Dawley rats were intratracheally (IT) instilled with saline, DEPs (35 mg/kg), or DEPEs (equivalent to 35 mg DEP/kg), with or without further treatment with an iNOS inhibitor, aminoguanidine (AG; 100 mg/kg), by intraperitoneal injection 30 min before and 3, 6, and 9 hr after IT exposure. At 1 day postexposure, both DEPs and DEPEs induced iNOS expression and NO production by AMs. AG significantly lowered DEP- and DEPE-induced iNOS activity but not the protein level while attenuating DEPE- but not DEP-mediated pulmonary inflammation, airway damage, and oxidant generation by AMs. DEP or DEPE exposure resulted in elevated secretion of both interleukin (IL) -12 and IL-10 by AMs. AG significantly reduced DEP- and DEPE-activated AMs in IL-12 production. In comparison, AG inhibited IL-10 production by DEPE-exposed AMs but markedly increased its production by DEP-exposed AMs, suggesting that NO differentially regulates the pro- and antiinflammatory cytokine balance in the lung. Both DEPs and DEPEs induced CYP1A1 expression. AG strongly inhibited CYP1A1 activity and lung S9 activity-dependent 2-aminoanthracene mutagenicity. These studies show that NO plays a major role in DEPE-induced lung inflammation and CYP-dependent mutagen activation but a lesser role in particulate-induced inflammatory damage.

RGD Manual Disease Annotations    Click to see Annotation Detail View

Objects Annotated

Genes (Rattus norvegicus)
Cyp1a1  (cytochrome P450, family 1, subfamily a, polypeptide 1)
Cyp2b1  (cytochrome P450, family 2, subfamily b, polypeptide 1)
Nos2  (nitric oxide synthase 2)

Genes (Mus musculus)
Cyp1a1  (cytochrome P450, family 1, subfamily a, polypeptide 1)
Cyp2b10  (cytochrome P450, family 2, subfamily b, polypeptide 10)
Nos2  (nitric oxide synthase 2, inducible)

Genes (Homo sapiens)
CYP1A1  (cytochrome P450 family 1 subfamily A member 1)
NOS2  (nitric oxide synthase 2)


Additional Information