Cytochrome P450-mediated pulmonary metabolism of carcinogens: regulation and cross-talk in lung carcinogenesis

Our plain-English summary of Cytochrome P450-mediated pulmonary metabolism of carcinogens: regulation and cross-talk in lung carcinogenesis, by S. Anttila, H. Raunio, J. Hakkola (American Journal of Respiratory Cell and Molecular Biology, 2011).

The study

• Authors: S. Anttila, H. Raunio, J. Hakkola
• Journal: American Journal of Respiratory Cell and Molecular Biology
• Published: 2011;44(5):583-90
• Type of article: Review
• Cited by: 66 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Lung cancer is strongly associated with exogenous risk factors, in particular tobacco smoking and asbestos exposure. New research data are accumulating about the regulation of the metabolism of tobacco carcinogens and the metabolic response to oxidative stress. These data provide mechanistic details about why well known risk factors cause lung cancer. The purpose of this review is to evaluate the present knowledge of the role of cytochrome P450 (CYP) enzymes in the metabolism of tobacco carcinogens and associations with tobacco and asbestos carcinogenesis. Major emphasis is placed on human data and regulatory pathways involved in CYP regulation and lung carcinogenesis. The most exciting new research findings concern cross-talk of the CYP-regulating aryl hydrocarbon receptor with other transcription factors, such as nuclear factor-erythroid 2-related factor 2, involved in the regulation of xenobiotic metabolism and antioxidant enzymes. This cross-talk between transcription factors may provide mechanistic evidence for clinically relevant issues, such as differences in lung cancers between men and women and the synergism between tobacco and asbestos as lung carcinogens.

In plain English

This article is a review, not new research. The authors summarized research on lung cytochrome P450 (CYP) enzymes, which process cancer-causing tobacco smoke chemicals, mainly polycyclic aromatic hydrocarbons (PAHs) and tobacco-specific nitrosamines. They described which CYP enzymes occur in human lung and how their production is regulated, noting that their actual function there is much less known. They described how the aryl hydrocarbon receptor (AHR), a control protein, interacts with others, including the estrogen receptor and NRF2. On asbestos, it stated that asbestos and smoking act synergistically on lung cancer risk, by mechanisms not fully known. It said DNA damage from reactive oxygen species is considered the principal way asbestos causes cancer. It cited reports that loss of chromosome 19p, where the KEAP1 gene lies, is very common in lung adenocarcinomas and especially in asbestos-related lung carcinomas. It said whether NRF2 and KEAP1 mutations are more frequent in asbestos-related cancer is unknown. The authors concluded that cross-talk between such control proteins may provide mechanistic evidence for the tobacco and asbestos synergism and for lung cancer differences between men and women.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review of published research
• Who was studied: No study population of its own. The authors reviewed published laboratory studies on human lung tissue and human lung cell lines, plus some mouse studies. In the section on enzyme regulation, only human CYP enzymes are discussed.
• Exposure: Tobacco smoke carcinogens, mainly PAHs and tobacco-specific nitrosamines such as NNK and NNN, and asbestos (no fiber type specified), considered through its link with oxidative stress and its combined effect with smoking on lung cancer
• Main results:
  • The review describes which CYP enzymes are expressed in human lung and how their expression is regulated. It states that much of this information comes from detecting the enzymes' mRNA and protein, and much less is known about their true function in lung tissue.
  • The review states that DNA damage caused by reactive oxygen species is considered the principal mechanism of asbestos carcinogenesis, citing earlier work.
  • The review describes the interaction between the AHR and NRF2 pathways as possibly providing a molecular basis for the strong synergism of tobacco smoking and asbestos exposure in lung cancer.
  • Citing earlier studies, the review states that loss of chromosome 19p, where the KEAP1 gene is located, is very common in lung adenocarcinomas and especially in asbestos-related lung carcinomas.
  • The review states it is not known whether NRF2 and KEAP1 mutations are more frequent in asbestos-related cancer than in other lung cancers.
  • The review suggests NF-kB may be one of the mediators between tobacco and asbestos carcinogenesis, because NF-kB is known to coordinate inflammatory and cell growth responses to asbestos.
  • An earlier study cited in the review (reference 5) observed higher CYP1A1 expression in normal lung tissue of female smokers than of male smokers, but no such difference for the other genes studied.
• The authors' conclusion: The authors concluded that cross-talk between transcription factors such as AHR and NRF2 may provide mechanistic evidence for clinically relevant issues, including differences in lung cancers between men and women and the synergism between tobacco and asbestos as lung carcinogens. They also concluded that changes leading to constant NRF2 activation, including loss of 19p13 and KEAP1 and NRF2 mutations, have been detected in human lung cancer and may let cancer cells avoid cell death.
• Limitations the authors state:
  • Much of the available information on lung CYP enzymes is limited to detecting their mRNA and protein. Much less is known about how the enzymes actually function in lung tissue.
  • The exact mechanism of the interaction between the AHR and NRF2 pathways is not known.
  • More information is needed from animal models because there are extensive differences between species.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Carcinogenesis, Lung Cancer, Asbestos Exposure, Oxidative Stress.

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