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.

Aldehyde dehydrogenase (ALDH) isozyme I deficiency in hair root samples from 105 healthy individuals and 72 alcoholics was determined using isoelectric focusing. From these individuals, 12 male alcoholics (2 with ALDH isozyme I deficiency and 10 normal) and 45 healthy controls (18 with ALDH isozyme I deficiency and 27 normal) were investigated for their blood ethanol and acetaldehyde levels by gas chromatography after an acute dose of alcohol (0.5 g ethanol/kg body wt.). Peak blood ethanol values of about 10 mmol/l were attained after 1 hour both in alcoholics and normal controls irrespective of their ALDH type. There was no significant difference in the blood ethanol level during the 5 hr post-drinking period in both the groups. Peak blood acetaldehyde concentration was significantly higher in healthy controls and alcoholics deficient in ALDH isozyme I after alcohol drinking (about 30 micro-mmol/l) than in individuals with normal ALDH isozyme I (3 micro-mmol/l). However, no significant difference in blood acetaldehyde was observed between alcoholics and controls.

Blood ethanol and acetaldehyde levels in Japanese alcoholics and controls.

Basis of aldehyde dehydrogenase deficiency in Orientals: immunochemical studies.

The metabolism of acetaldehyde has received considerable attention in the past few years due to its toxic effects and possible importance in pharmacogenetics. Recent studies have demonstrated rapid progress concerning the multiple molecular forms of ADH and ALDH and their genetic variants. The isozymes of ALDH may play an important role in the biological sensitivity to alcohol in certain ethnic groups and also in the pathogenesis of alcohol related organ damage. A protective effect of ALDH I deficiency against alcoholism seems to exist in Japanese.

Pharmacogenetics of alcohol sensitivity.

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Shoji Harada and Dharam P. Agarwal. The presentations were (1) Mutations in the exons, exon-intron junctions, and promoter regions of human CYP2E1 gene and alcoholism, by Fumio Nomura; (2) Genetic variability in alcohol metabolism and drinking habits in Japanese, by Shoji Harada; (3) Genetic studies of alcohol dependence using alcoholics with inactive ALDH2, by Susumu Higuchi; and (4) Alcohol consumption, apolipoprotein polymorphisms, and cardiovascular disorders, by Dharam P. Agarwal.

Metabolic and Ethnic Determinants of Alcohol Drinking Habits and Vulnerability to Alcohol‐Related Disorder

Alcoho l abuse and alcohol dependence pose serious human behavioral disorders in most of the developed as well as developing countries of the world. Besides socioeconomic, cultural, and biobehavioral factors, certain biological and environmental components are among the major determinants of alcohol-seeking behavior in a society [3, 26, 27]. A series of factors interact in predisposing or protecting an individual against alcoholism and alcohol-related disorders: the availability of alcohol and its price, an individual's sociocultural, psychological, physiological, and genetic make-up. The three alcoholic subtypes described by Bohman et al. [9] may represent a cluster of different metabolic and mental disorders and behavioral traits grouped together artificially by a \"clinical model\" of alcoholism. Family, twin, and adoption studies unambiguously indicate a genetic basis for the familial aggregation of alcoholism [5, 27]. To understand the nature of the susceptibility factors responsible for the development of alcoholism, elucidation of the following aspects, among others, is essential: (a) predisposing factors which influence alcohol drinking habits; (b) genetic vulnerability to acute toxic effects of alcohol; and (c) variations in alcohol metabolism. Liver alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), primarily responsible for the oxidative degradation of ethanol and acetaldehyde, respectively, are genetically polymorphic [4].

Medicobiological and genetic studies on alcoholism. Role of metabolic variation and ethnicity on drinking habits, alcohol abuse and alcohol-related mortality.

Dharam P. Agarwal

Papers

Blood ethanol and acetaldehyde levels in Japanese alcoholics and controls.

Basis of aldehyde dehydrogenase deficiency in Orientals: immunochemical studies.

Pharmacogenetics of alcohol sensitivity.

Metabolic and Ethnic Determinants of Alcohol Drinking Habits and Vulnerability to Alcohol‐Related Disorder

Medicobiological and genetic studies on alcoholism. Role of metabolic variation and ethnicity on drinking habits, alcohol abuse and alcohol-related mortality.