Integration of hepatic drug transporters and phase II metabolizing enzymes: Mechanisms of hepatic excretion of sulfate, glucuronide, and glutathione metabolites

The liver is the primary site of drug metabolism in the body. Typically, metabolic conversion of a drug results in inactivation, detoxification, and enhanced likelihood for excretion in urine or feces. Sulfation, glucuronidation, and glutathione conjugation represent the three most prevalent classes of phase II metabolism, which may occur directly on the parent compounds that contain appropriate structural motifs, or, as is usually the case, on functional groups added or exposed by phase I oxidation. These three conjugation reactions increase the molecular weight and water solubility of the compound, in addition to adding a negative charge to the molecule. As a result of these changes in the physicochemical properties, phase II conjugates tend to have very poor membrane permeability, and necessitate carrier-mediated transport for biliary or hepatic basolateral excretion into sinusoidal blood for eventual excretion into urine. This review summarizes sulfation, glucuronidation, and glutathione conjugation reactions, as well as recent progress in elucidating the hepatic transport mechanisms responsible for the excretion of these conjugates from the liver. The discussion focuses on alterations of metabolism and transport by chemical modulators, and disease states, as well as pharmacodynamic and toxicological implications of hepatic metabolism and/or transport modulation for certain active phase II conjugates. A brief discussion of issues that must be considered in the design and interpretation of phase II metabolite transport studies follows.     

Variation in DNA repair genes ERCC2, XRCC1, and XRCC3 and risk of follicular lymphoma.

The reasons for the positive association between skin cancer and non-Hodgkin's lymphoma are not known but may be due to common susceptibility involving suboptimal DNA repair. Therefore, we investigated selected polymorphisms and haplotypes in three DNA repair genes, previously associated with skin cancer and DNA repair capacity, in risk of follicular lymphoma, including possible gene interaction with cigarette smoking and sun exposure. We genotyped 19 single nucleotide polymorphisms (SNP) in the ERCC2, XRCC1, and XRCC3 genes in 430 follicular lymphoma patients and 605 controls within a population-based case-control study in Denmark and Sweden. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using unconditional logistic regression and haplotype associations were assessed with a global score test. We observed no associations between variation in the ERCC2 and XRCC1 genes and follicular lymphoma risk. In XRCC3, increased risk of follicular lymphoma was suggested for rare homozygotes of three SNPs [Rs3212024: OR, 1.8 (95% CI, 1.1-2.8); Rs3212038: OR, 1.5 (95% CI, 1.0-2.4); Rs3212090: OR, 1.5 (95% CI, 1.0-2.5)]. These results were strengthened in current cigarette smokers. However, evidence of differences in XRCC3 haplotype distributions between follicular lymphoma cases and controls was weak, both overall and in current smokers. We conclude that polymorphic variation in the XRCC3 gene, but not in ERCC2 or XRCC1, may be of importance for susceptibility to follicular lymphoma, perhaps primarily in current smokers. The link between skin cancer and follicular lymphoma is unlikely to be mediated through common variation in the studied DNA repair gene polymorphisms.     

Effect of soy phytoestrogens on hot flashes in postmenopausal women with breast cancer: a randomized, controlled clinical trial.

PURPOSE: Vasomotor symptoms, such as hot flashes and night sweats, in breast cancer survivors are often worsened by chemotherapy and tamoxifen, and/or the discontinuation of hormone replacement therapy at diagnosis. This study evaluated the acceptability and effectiveness of a soy beverage containing phytoestrogens as a treatment for hot flashes in postmenopausal women with breast cancer. METHODS: A randomized, placebo-controlled, double-blind clinical trial was conducted in postmenopausal women with moderate hot flashes who were previously treated for early-stage breast cancer. Women were stratified for tamoxifen use and randomized to a soy beverage (n = 59) containing 90 mg of isoflavones or to a placebo rice beverage (n = 64). Women recorded the number and severity of hot flashes daily with a daily menopause diary for 4 weeks at baseline and for 12 weeks while consuming 500 mL of a soy or placebo beverage. RESULTS: There were no significant differences between the soy and placebo groups in the number of hot flashes or hot flash scores. However, presumably because of a strong placebo effect, both groups had significant reductions in hot flashes. Mild gastrointestinal side effects were experienced by both groups but occurred with greater frequency and severity with soy. The mean serum genistein concentration at 6 weeks was significantly higher in women who consumed soy (0.61 +/- 0.43 micromol/L) compared with placebo (0.43 +/- 0.37 micromol/L) (P =.02). Overall acceptability and compliance were high and similar in both groups. CONCLUSION: The soy beverage did not alleviate hot flashes in women with breast cancer any more than did a placebo. Future research into other compounds is recommended to identify safe and effective therapies for hot flashes in breast cancer survivors.     

Is there a role for Notch signalling in human breast cancer?

Aberrant Notch signalling has been observed in several human cancers, including acute T-cell lymphoblastic leukaemia and cervical cancer, and is strongly implicated in tumourigenesis. Unregulated Notch signalling in the mouse mammary gland leads to tumour formation. These results raise the possibility that Notch signalling might play a role in human breast cancer. There are currently few reports that address this question directly and this appears to be an area worthy of further investigation.     

Comparison of vaginal length after iliococcygeus fixation and sacrospinous ligament fixation

OBJECTIVE: To compare vaginal length after iliococcygeus fixation (ICF) and sacrospinous ligament fixation (SSLF). METHODS: A retrospective cohort study was performed on patients undergoing ICF or SSLF. Sixty-seven patients were identified and, of these, only 46 had complete data sets, leaving 23 patients in either group eligible for study. RESULTS: There were no significant differences in demographic data between the 2 groups. Mean vaginal length measurements were not significantly different before and after the ICF procedure (7.7+/-0.9 cm vs 7.6+/-0.8 cm, respectively; P=0.68). However, the mean vaginal length was significantly shortened following SSLF (7.9+/-0.8 cm vs 7.1+/-1.1 cm, P=0.001). The mean vaginal lengths preoperatively (7.7+/-0.9 cm vs 7.9+/-0.8 cm, P=0.51) and postoperatively (7.6+/-0.8 cm vs 7.1+/-1.1 cm, P=0.07) were similar. CONCLUSION: Iliococcygeus fixation does not significantly shorten vaginal length at the time of vaginal vault suspension, whereas the sacrospinous ligament fixation procedure does shorten vaginal length.     

The changing pattern of infant mortality in the US: The role of prenatal factors and their obstetrical implications

Infant mortality is one of the leading public health problems in the United States today. During the first half of this century the decline in infant mortality resulted largely from a reduction in postneonatal deaths (2–11 months after birth). Since 1950, two-thirds of all infant deaths have occurred in the neonatal period (1st month after birth). Since 1981, the rate of decline in the infant mortality rate has slowed due to a deterioration in the distribution of birthweights and a slowed improvement in birthweight-specific mortality rates. The role of birthweight is central to this issue, because low birthweight (LBW, < 2500 g) is a major determinant of death in the first year of life, particularly during the neonatal period. Stated another way, less than 0.5% of infants with birthweights > 2500 g die during the first year of life compared to 10.2% of infants with birthweights <2500 g and 45.3% with birthweights < 1500 g (very low birthweight, VLBW). These effects are magnified when evaluated on a race-specific basis: the rate of LBW is twice as high and the rate of VLBW is three times as high for black infants compared to white infants. Reducing the rates of VLBW and LBW, particularly among blacks, holds the greatest potential for future reductions in infant mortality in the United States. The important role of maternal factors in the antecedents of infant mortality (VLBW, LBW, intrauterine growth retardation, preterm birth) have been clearly and repeatedly demonstrated. Some of these factors, such as maternal race, adverse obstetrical history and low level of education, are not amenable to change during pregnancy. Other factors, such as cessation of smoking, higher maternal weight gain and the initiation of early prenatal care have been shown to improve the course and outcome of pregnancy and subsequently result in reduced infant mortality.     

Inhaled crocidolite mutagenicity in lung DNA

We used transgenic mice carrying the lacI reporter gene to study the mutagenesis potential of asbestos crocidolite. The animals were exposed by nose-only inhalation to an aerosol containing 5.75 mg/m(3) crocidolite dust for 6 hr/day and 5 consecutive days. After 1, 4, and 12 weeks, we examined four end points: the cytology of bronchoalveolar lavage, the lung load of crocidolite, the hydrophobic DNA adducts, and the mutations in the lacI reporter gene. Twelve weeks after exposure, nearly 10% of the inhaled fibers remained in the lung (227 +/- 103 ng/mg lung). There was evidence of a typical inflammatory response consisting of multinucleate macrophages at weeks 4 and 12, whereas immediately after the exposure, we observed numerous polymorphonuclear neutrophils. The mutant frequency significatively increased during the fourth week after the exposure: 13.5 [time] 10(-5) in the exposed group versus 6. 9 10(-5) in the control group. The induction factor, defined by the ratio of checked mutants of exposed mice to checked mutants of control mice, was 1.96. The mutation spectrum of control lung DNA and exposed lung DNA was similar, suggesting the possible involvement of a DNA repair decrease in crocidolite-treated animals. We used the (32)P-postlabeling method and did not detect any increase of either 5 mC or bulky adduct in treated mice. This is the first study that demonstrates asbestos mutagenicity in vivo after a nose-only inhalation.