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. 2010 Mar 19;184(1-2):222-8.
doi: 10.1016/j.cbi.2009.11.017. Epub 2009 Nov 24.

Relationships between metabolic and non-metabolic susceptibility factors in benzene toxicity

David Ross  1 , Hongfei Zhou
Affiliations

Relationships between metabolic and non-metabolic susceptibility factors in benzene toxicity

David Ross et al. Chem Biol Interact. .

Abstract

Reactive metabolites formed from benzene include benzene oxide, trans,trans muconaldehyde, quinones, thiol adducts, phenolic metabolites and oxygen radicals. Susceptibility to the toxic effects of benzene has been suggested to occur partly because of polymorphisms in enzymes involved in benzene metabolism which include cytochrome P450 2E1, epoxide hydrolases, myeloperoxidase, glutathione-S-transferases and quinone reductases. However, susceptibility factors not directly linked to benzene metabolism have also been associated with its toxicity and include p53, proteins involved in DNA repair, genomic stability and expression of cytokines and/or cell adhesion molecules. In this work, we examine potential relationships between metabolic and non-metabolic susceptibility factors using the enzyme NAD(P)H:quinone oxidoreductase (NQO1) as an example. NQO1 may also impact pathways in addition to metabolism of quinones due to protein-protein interactions or other mechanisms related to NQO1 activity. NQO1 has been implicated in stabilizing p53 and in maintaining microtubule integrity. Inhibition or knockdown of NQO1 in bone marrow endothelial cells has been found to lead to deficiencies of E-selectin, ICAM-1 and VCAM-1 adhesion molecule expression after TNFalpha stimulation. These examples illustrate how the metabolic susceptibility factor NQO1 may influence non-metabolic susceptibility pathways for benzene toxicity.

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Figures

Figure 1
Figure 1. Benzene metabolic scheme
Most Phase II pathways have been omitted. For potential reactive metabolites, see Table 1. For metabolic susceptibility factors, see Table 2. Adapted from [7],[10].
Figure 2
Figure 2. Metabolic susceptibility factors in stroma (MPO/NQO1/GSH)
Metabolic factors such as MPO, NQO1 and GSH can influence cell specific toxicity of benzene metabolites.
Figure 3
Figure 3. Mechanisms of HQ induced inhibition of tube formation in HBMEC
An important role for ChM-I.
Figure 4
Figure 4. The metabolic susceptibility factor NQO1 influences other non-metabolic susceptibility factors
NQO1 modulates p53 stability and adhesion molecule expression.
See this image and copyright information in PMC

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