Estimates of the worldwide incidence, mortality and prevalence of 26 cancers in the year 2002 are now available in the GLOBOCAN series of the International Agency for Research on Cancer. The results are presented here in summary form, including the geographic variation between 20 large "areas" of the world. Overall, there were 10.9 million new cases, 6.7 million deaths, and 24.6 million persons alive with cancer (within three years of diagnosis). The most commonly diagnosed cancers are lung (1.35 million), breast (1.15 million), and colorectal (1 million); the most common causes of cancer death are lung cancer (1.18 million deaths), stomach cancer (700,000 deaths), and liver cancer (598,000 deaths). The most prevalent cancer in the world is breast cancer (4.4 million survivors up to 5 years following diagnosis). There are striking variations in the risk of different cancers by geographic area. Most of the international variation is due to exposure to known or suspected risk factors related to lifestyle or environment, and provides a clear challenge to prevention.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.3322/canjclin.55.2.74

Global cancer statistics, 2002.

The authors suggest that the most promising route to effective strategies for the prevention of adolescent alcohol and other drug problems is through a risk-focused approach. This approach requires the identification of risk factors for drug abuse, identification of methods by which risk factors have been effectively addressed, and application of these methods to appropriate high-risk and general population samples in controlled studies. The authors review risk and protective factors for drug abuse, assess a number of approaches for drug abuse prevention potential with high-risk groups, and make recommendations for research and practice.

/pdf/risk-and-protective-factors-for-alcohol-and-other-drug-ubehfds1zo.pdf

Risk and protective factors for alcohol and other drug problems in adolescence and early adulthood: Implications for substance abuse prevention.

The glutathione S-transferases (GST) represent a major group of detoxification enzymes. All eukaryotic species possess multiple cytosolic and membrane-bound GST isoenzymes, each of which displays distinct catalytic as well as noncatalytic binding properties: the cytosolic enzymes are encoded by at least five distantly related gene families (designated class alpha, mu, pi, sigma, and theta GST), whereas the membrane-bound enzymes, microsomal GST and leukotriene C, synthetase, are encoded by single genes and both have arisen separately from the soluble GST. Evidence suggests that the level of expression of GST is a crucial factor in determining the sensitivity of cells to a broad spectrum of toxic chemicals. In this article the biochemical functions of GST are described to show how individual isoenzymes contribute to resistance to carcinogens, antitumor drugs, environmental pollutants, and products of oxidative stress.A description of the mechanisms of transcriptional and posttranscriptional regulat...

The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance.

Observational epidemiological studies suffer from many potential biases, from confounding and from reverse causation, and this limits their ability to robustly identify causal associations. Several high-profile situations exist in which randomized controlled trials of precisely the same intervention that has been examined in observational studies have produced markedly different findings. In other observational sciences, the use of instrumental variable (IV) approaches has been one approach to strengthening causal inferences in non-experimental situations. The use of germline genetic variants that proxy for environmentally modifiable exposures as instruments for these exposures is one form of IV analysis that can be implemented within observational epidemiological studies. The method has been referred to as 'Mendelian randomization', and can be considered as analogous to randomized controlled trials. This paper outlines Mendelian randomization, draws parallels with IV methods, provides examples of implementation of the approach and discusses limitations of the approach and some methods for dealing with these.

/pdf/mendelian-randomization-using-genes-as-instruments-for-2tocar3o2g.pdf

Mendelian randomization: using genes as instruments for making causal inferences in epidemiology.

Electrophiles formed during metabolic activation of chemical carcinogens and reactive oxygen species generated from endogenous and exogenous sources play a significant role in carcinogenesis. Cancer chemoprevention by induction of phase 2 proteins to counteract the insults of these reactive intermediates has gained considerable attention. Nuclear factor E2 p45-related factor 2 (Nrf2), a bZIP transcription factor, plays a central role in the regulation (basal and or inducible expression) of phase 2 genes by binding to the “antioxidant response element” in their promoters. Identification of novel Nrf2-regulated genes is likely to provide insight into cellular defense systems against the toxicities of electrophiles and oxidants and may define effective targets for achieving cancer chemoprevention. Sulforaphane is a promising chemopreventive agent that exerts its effect by strong induction of phase 2 enzymes via activation of Nrf2. In the present study, a transcriptional profile of small intestine of wild-type (nrf2 +/+) and knock out (nrf2 −/−) mice treated with vehicle or sulforaphane (9 μmol/day for 1 week, p.o.) was generated using the Murine Genome U74Av2 oligonucleotide array (representing ∼6000 well-characterized genes and nearly 6000 expressed sequence tags). Comparative analysis of gene expression changes between different treatment groups of wild-type and nrf2-deficient mice facilitated identification of numerous genes regulated by Nrf2 including previously reported Nrf2-regulated genes such as NAD(P)H:quinone reductase (NQO1), glutathione S-transferase (GST), γ-glutamylcysteine synthetase (GCS), UDP-glucuronosyltransferases (UGT),epoxide hydrolase, as well as a number of new genes. Also identified were genes encoding for cellular NADPH regenerating enzymes (glucose 6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, and malic enzyme), various xenobiotic metabolizing enzymes, antioxidants (glutathione peroxidase, glutathione reductase, ferritin, and haptaglobin), and biosynthetic enzymes of the glutathione and glucuronidation conjugation pathways. The data were validated by Northern blot analysis and enzyme assays of selected genes. This investigation expands the horizon of Nrf2-regulated genes, highlights the cross-talk between various metabolic pathways, and divulges the pivotal role played by Nrf2 in regulating cellular defenses against carcinogens and other toxins.

https://cancerres.aacrjournals.org/content/canres/62/18/5196.full.pdf

Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray.

The distribution of the human liver alcohol dehydrogenase, ADH2, and aldehyde dehydrogenase, ALDH2, genotypes in 21 different populations comprising Mongoloids, Caucasoids, and Negroids was determined by hybridization of the amplified genomic DNA with allele-specific oligonucleotide probes. Whereas the frequency of the ADH1(2) allele was found to be relatively high in the Caucasoids, Mexican Mestizos, Brazilian Indios, Swedish Lapps, Papua New Guineans and Negroids, the frequency of the ADH2(2) gene was considerably higher in the Mongoloids and Australian Aborigines. The atypical ALDH2 gene (ALDH2(2)) was found to be extremely rare in Caucasoids, Negroids, Papua New Guineans, Australian Aborigines and Aurocanians (South Chile). In contrast, this mutant gene was found to be widely prevalent among the Mongoloids. Individuals possessing the abnormal ALDH2 gene show alcohol-related sensitivity responses (e.g. facial flushing), have the tendency not to be habitual drinkers, and apparently suffer less from alcoholism and alcohol-related liver disease.

Distribution of ADH2 and ALDH2 genotypes in different populations

There is abundant epidemiological and clinical evidence showing that light-moderate drinking is associated with a reduced risk of coronary heart disease (CHD), total and ischaemic stroke and total mortality in middle-aged and elderly men and women. The epidemiological evidence suggests a J- or U-shaped relationship between alcohol and CHD. However, the apparent benefits of moderate drinking on CHD mortality are offset at higher drinking levels by increasing risk of death from other types of heart diseases (cardiomyopathy, arrhythmia etc.), neurological disorders, cancer, liver cirrhosis, and traffic accidents. The plausible mechanisms for the putative cardioprotective effects include increased levels of high-density lipoprotein cholesterol, decreased levels of low-density lipoprotein cholesterol, prevention of clot formation, reduction in platelet aggregation, and lowering of plasma apolipoprotein(a) concentration. Thus, alcohol reduces the risk of coronary vascular diseases both by inhibiting the formation of atheroma and decreasing the rate of blood coagulation.

/pdf/cardioprotective-effects-of-light-moderate-consumption-of-3bulnhzisr.pdf

Cardioprotective effects of light-moderate consumption of alcohol: a review of putative mechanisms.

A hypothesis regarding alcohol sensitivity in Japanese due to a polymorphism of liver aldehyde dehydrogenase (ALDH) is presented. ALDH was found to show two major bands, a faster migrating isozyme with a low Km for acetaldehyde and a slower migrating isozyme with a high Km for acetaldehyde. Out of 40 livers of Japanese, 21 had only the slower migrating isozyme. No such variation was detected in 68 autopsy livers of Germans. Our data suggest that the initial alcohol sensitivity, quite common in individuals of Mongoloid origin, might be due to a delayed oxidation of acetaldehyde rather than its higher than normal production by atypical alcohol dehydrogenase.

Racial differences in alcohol sensitivity: A new hypothesis

Electrophoretic and kinetic studies of autopsy liver specimens from individuals of different racial groups revealed a polymorphism in alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). About 85% of the Japanese livers had an atypical ADH and 52% of the livers an unusual ALDH. Only 13% of German liver specimens had the atypical ADH and none showed the unusual form of ALDH which lacks in the isozyme with low Km for acetaldehyde. Using hair roots as the source of ADH and ALDH, individuals showing sensitivity to ethanol were examined. Data on the distribution of phenotypes in random European and Japanese population as well as family studies suggest a direct relationship between the lack of low Km isozyme of ALDH and alcohol-induced biological sensitivity. Our findings suggest that the alcohol sensitivity quite common in individuals of Mongoloid origin might be due to delayed oxidation of acetaldehyde by an unusual type of ALDH.

Racial differences in biological sensitivity to ethanol: the role of alcohol dehydrogenase and aldehyde dehydrogenase isozymes

The pharmacogenetic differences among individuals in their capacity to metabolize ingested alcohol are possibly responsible for the large inter-individual and inter-ethnic variations observed in the outcome of alcohol use and misuse. Based on results of adoption, twin, and family studies it is now w

Dharam P. Agarwal

Papers

Distribution of ADH2 and ALDH2 genotypes in different populations

Cardioprotective effects of light-moderate consumption of alcohol: a review of putative mechanisms.

Racial differences in alcohol sensitivity: A new hypothesis

Racial differences in biological sensitivity to ethanol: the role of alcohol dehydrogenase and aldehyde dehydrogenase isozymes

Pharmacogenetics of alcohol metabolism and alcoholism.