Populations and genetic polymorphisms*

Weber, Wendell W.

doi:10.1016/s1084-8592(99)80006-x

Cited by 87 publications

(44 citation statements)

References 32 publications

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“…One is because of potential biological differences. There is evidence to indicate that random distribution of allele frequencies throughout the human genome follows diverse ethnic and/or racial trends (39,40). The frequency of sequence variation can differ by race and ethnicity, and this variation may be associated with a difference in risk for disease between these groups (41).…”

Section: Discussionmentioning

confidence: 99%

Less Efficient G2-M Checkpoint Is Associated with an Increased Risk of Lung Cancer in African Americans

Zheng

Loffredo

Alberg³

et al. 2005

Cancer Research

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Cell cycle checkpoints play critical roles in the maintenance of genomic integrity. The inactivation of checkpoint genes by genetic and epigenetic mechanisms is frequent in all cancer types, as a less-efficient cell cycle control can lead to genetic instability and tumorigenesis. In an on-going case-control study consisting of 216 patients with non-small cell lung cancer, 226 population-based controls, and 114 hospital-based controls, we investigated the relationship of ;-radiationinduced G 2 -M arrest and lung cancer risk. Peripheral blood lymphocytes were cultured for 90 hours, exposed to 1.0 Gy ;-radiation, and harvested at 3 hours after ;-radiation treatment. ;-Radiation-induced G 2 -M arrest was measured as the percentage of mitotic cells in untreated cultures minus the percentage of mitotic cells in ;-radiation-treated cultures from the same subject. The mean percentage of ;-radiation-induced G 2 -M arrest was significantly lower in cases than in population controls (1.18 versus 1.44, P < 0.01) and hospital controls (1.18 versus 1.40, P = 0.01). When dichotomized at the 50th percentile value in combined controls (population and hospital controls), a lower level of ;-radiation-induced G 2 -M arrest was associated with an increased risk of lung cancer among African Americans after adjusting for baseline mitotic index, age, gender, and pack-years of smoking [adjusted odd ratio (OR), 2.25; 95% confidence interval (95% CI), 0.97-5.20]. A significant trend of an increased risk of lung cancer with a decreased level of G 2 -M arrest was observed (P trend = 0.02) among African Americans, with a lowest-versus-highest quartile adjusted OR of 3.74 (95% CI, 0.98-14.3). This trend was most apparent among African American females (P trend < 0.01), with a lowest-versushighest quartile adjusted OR of 11.75 (95% CI, 1.47-94.04). The results suggest that a less-efficient DNA damage-induced G 2 -M checkpoint is associated with an increased risk of lung cancer among African Americans. Interestingly, we observed a stronger association of DNA damage-induced G 2 -M arrest and lung cancer among African Americans when compared with Caucasians. If replicated, these results may provide clues to the exceedingly high lung cancer incidence experienced by African Americans. (Cancer Res 2005; 65(20): 9566-73)

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Section: Discussionmentioning

confidence: 99%

Less Efficient G2-M Checkpoint Is Associated with an Increased Risk of Lung Cancer in African Americans

Zheng

Loffredo

Alberg³

et al. 2005

Cancer Research

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“…Patients with inactive CYP2D6 are at risk of toxicity from agents that are usually metabolised by this isoenzyme. Polymorphism of CYP2C9 and CYP2C19 accounts for the variable metabolism of some AEDs, including PHT (37)(38)(39). The frequency of mutations of the CYP2C9 gene is much higher in whites than in Japanese or other Asians, whereas the frequency of mutations of the CYP2C19 gene is much higher in Japanese than in whites (37,40).…”

Section: Genetic Polymorphismmentioning

confidence: 99%

The Importance of Drug Interactions in Epilepsy Therapy

et al. 2002

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Summary: Long-term antiepileptic drug (AED) therapy is the reality for the majority of patients diagnosed with epilepsy. One AED will usually be sufficient to control seizures effectively, but a significant proportion of patients will need to receive a multiple AED regimen. Furthermore, polytherapy may be necessary for the treatment of concomitant disease. The fact that over-the-counter drugs and nutritional supplements are increasingly being self-administered by patients also must be considered. Therefore the probability of patients with epilepsy experiencing drug interactions is high, particularly with the traditional AEDs, which are highly prone to drug interactions. Physicians prescribing AEDs to patients with epilepsy must, therefore, be aware of the potential for drug interactions and the effects (pharmacokinetic and pharmacodynamic) that can occur both during combination therapy and on drug discontinuation. Although pharmacokinetic interactions are numerous and well described, pharmacodynamic interactions are few and usually concluded by default. Perhaps the most clinically significant pharmacodynamic interaction is that of lamotrigine (LTG) and valproic acid (VPA); these drugs exhibit synergistic efficacy when coadministered in patients with refractory partial and generalised seizures. Hepatic metabolism is often the target for pharmacokinetic drug interactions, and enzyme-inducing drugs such as phenytoin (PHT), phenobarbitone (PB), and carbamazepine (CBZ) will readily enhance the metabolism of other AEDs [e.g., LTG, topiramate (TPM), and tiagabine (TGB)].The enzyme-inducing AEDs also enhance the metabolism of many other drugs (e.g., oral contraceptives, antidepressants, and warfarin) so that therapeutic efficacy of coadministered drugs is lost unless the dosage is increased. VPA inhibits the metabolism of PB and LTG, resulting in an elevation in the plasma concentrations of the inhibited drugs and consequently an increased risk of toxicity. The inhibition of the metabolism of CBZ by VPA results in an elevation of the metabolite CBZepoxide, which also increases the risk of toxicity. Other examples include the inhibition of PHT and CBZ metabolism by cimetidine and CBZ metabolism by erythromycin. In recent years, a more rational approach has been taken with regard to metabolic drug interactions because of our enhanced understanding of the cytochrome P450 system that is responsible for the metabolism of many drugs, including AEDs. The review briefly discusses the mechanisms of drug interactions and then proceeds to highlight some of the more clinically relevant drug interactions between AEDs and between AEDs and non-AEDs. Understanding the fundamental principles that contribute to a drug interaction may help the physician to better anticipate a drug interaction and allow a graded and planned therapeutic response and, therefore, help to enhance the management of patients with epilepsy who may require treatment with polytherapy regimens.

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“…For a few drugs, evidence exists for these as underlying causes of idiosyncrasy. An example is the proposed importance of acetylation polymorphism in the toxic responses to hydrazines and aromatic amine drugs, such as isoniazid (INH; Stevens et al, 1999;Weber, 1999). INH causes hepatotoxicity in Ͻ10% of patients taking the drug.…”

Section: Modes and Mechanisms: Conventional Wisdommentioning

confidence: 99%

Inflammation and Drug Idiosyncrasy—Is There a Connection?

Roth

Luyendyk²,

Maddox

et al. 2003

J Pharmacol Exp Ther

122

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"Drug idiosyncrasy" refers to untoward reactions to drugs that occur in a small fraction of patients and have no obvious relationship to dose or duration of therapy. The liver is a frequent target for toxicity. Much of the conventional thinking about mechanisms of drug idiosyncrasy has centered on hypotheses that the reactions have a metabolic basis involving drug metabolism polymorphisms or that they arise from a specific immune response to the drug or its metabolite(s). For very few drugs does convincing evidence exist for either of these mechanisms, however. The erratic temporal and dose relationships that characterize idiosyncratic drug responses suggest the possibility that some event during the course of therapy renders tissues peculiarly susceptible to toxic effects of the drug. For example, episodes of inflammation are commonplace in people, and results of numerous studies in animals indicate that a modest inflammatory response can enhance tissue sensitivity to a variety of toxic chemicals. These observations have led to the hypothesis that an episode of inflammation during drug therapy could decrease the threshold for drug toxicity and thereby render an individual susceptible to a toxic reaction that would not otherwise occur (i.e., an "idiosyncratic" response). This hypothesis can explain the features of drug idiosyncrasy using fundamental pharmacologic principles, and results of recent animal studies are supportive of this. Knowledge gaps that need to be filled before the hypothesis should be widely accepted are discussed.

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Populations and genetic polymorphisms*

Cited by 87 publications

References 32 publications

Less Efficient G2-M Checkpoint Is Associated with an Increased Risk of Lung Cancer in African Americans

Less Efficient G2-M Checkpoint Is Associated with an Increased Risk of Lung Cancer in African Americans

The Importance of Drug Interactions in Epilepsy Therapy

Inflammation and Drug Idiosyncrasy—Is There a Connection?

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