Role of cytochrome P4502E1 in alcoholic liver disease pathogenesis

The intragastric tube feeding model is ideal for the study of the role of dietary factors and the effect of drugs on experimental alcoholic liver disease (ALD), since the model allows us to study the effect of a single variable in the diet on the pathology of liver where the blood alcohol level (BAL) is maintained over 150 mg%. By varying the dietary fatty acid composition we showed that the pathology was worsened by increasing linoleic acid or polyunsaturated fatty acids (PUFAs) in the diet where cytochrome P4502E1 (CYP2E1) was increased posttranslationally by high BAL. Concomitant with the increase in CYP2E1 there was evidence for an increase in lipid peroxidation (LP) by microsomes. Protein adducts of the products of LP were increased in the blood. Isoniazid (INH) enhanced this process and the pathology of ALD when INH was fed at therapeutic levels with ethanol. Preliminary studies show that diallyl sulfide, which inhibits and destroys liver CYP2E1 selectively, also modified the pathologic effects of ethanol. Thus we postulate that CYP2E1 induction plays a central role in the pathogenesis of ALD.     

Lipid Peroxidation and Vitamin E in Red Blood Cells and Plasma in Hemodialysis Patients Under rhEPO Treatment

Abstract: Lipid peroxidation, measured by malonyldial-dehyde (MDA) and vitamin E in red blood cells (RBC) and plasma, was investigated in 25 hemodialysis (HD) patients before and after 6 months rhEPO therapy. RBC-MDA was significantly elevated, but plasma MDA was in the reference range. After recombinant human erythro-poietin (rhEPO) treatment, the MDA level was significantly decreased in both compartments. Marked vitamin E deficiency was established in RBC as well as in plasma. rhEPO therapy restored vitamin E levels in both compartments. Our data suggest a possible positive rhEPO-antioxidant effect in HD patients.     

Heterocyclic amines: evaluation of their role in diet associated human cancer

1 Heterocyclic amines are formed in parts per billion levels when meat is cooked.
2 The heterocyclic amines MeIQx and PhIP are efficiently absorbed into the systemic circulation after ingestion of cooked food.
3 We have shown that MeIQx and PhIP, both in vitro and in vivo , are substrates for human hepatic CYP1A2, which exclusively and efficiently catalyses their conversion to genotoxic hydroxylamines.
4 MeIQx and PhIP are promutagens. MeIQx is a very powerful bacterial mutagen whereas PhIP is a more potent mammalian cell mutagen. Using a mammalian cell target gene, hprt , we have shown that PhIP induces a characteristic mutational 'fingerprint'.
5 MeIQx and PhIP are carcinogenic in bioassays. The PhIP mutational 'fingerprint' has been detected in the Apc gene of 5/8 colonic tumours induced by PhIP in rats.     

Population toxicokinetics of tetrachloroethylene

 In assessing the distribution and metabolism of toxic compounds in the body, measurements are not always feasible for ethical or technical reasons. Computer modeling offers a reasonable alternative, but the variability and complexity of biological systems pose unique challenges in model building and adjustment. Recent tools from population pharmacokinetics, Bayesian statistical inference, and physiological modeling can be brought together to solve these problems. As an example, we modeled the distribution and metabolism of tetrachloroethylene (PERC) in humans. We derive statistical distributions for the parameters of a physiological model of PERC, on the basis of data from Monster et al. (1979). The model adequately fits both prior physiological information and experimental data. An estimate of the relationship between PERC exposure and fraction metabolized is obtained. Our median population estimate for the fraction of inhaled tetrachloroethylene that is metabolized, at exposure levels exceeding current occupational standards, is 1.5% [95% confidence interval (0.52%, 4.1%)]. At levels approaching ambient inhalation exposure (0.001 ppm), the median estimate of the fraction metabolized is much higher, at 36% [95% confidence interval (15%, 58%)]. This disproportionality should be taken into account when deriving safe exposure limits for tetrachloroethylene and deserves to be verified by further experiments. Received: 20 April 1995/Accepted: 24 August 1995     

Can bone metabolism markers be adopted as an alternative to scintigraphic imaging in monitoring bone metastases from breast cancer?

Bone scintigraphy plays a major role in the diagnosis of bone metastases. The clinical utility of new biochemical markers of bone metabolism has recently been investigated in various bone diseases. This study evaluated the role of some bone metabolism markers in comparison with bone scan in the follow-up of breast cancer patients. We studied 149 patients with breast cancer, 33 (22%) of whom had bone metastases. IRMAs were used for the evaluation of blood levels of osteocalcin, bone alkaline phosphatase (BAP), the C-terminal propeptide of type I procollagen and the C-terminal cross-linked telopeptide of type I collagen (ICTP). Multivariate regression analysis showed that menopausal status (P=0.007) and metastatic bone lesions (P=0.001) affected bone marker levels. When considering post-menopausal women, the only subset in which bone metabolism marker behaviour could be reliably investigated, we found a high degree of overlap in marker distribution for scan-positive and scan-negative patients. Discrimination between scan-negative and scan-positive patients based on the above markers, taken singly or jointly, was assessed by means of logistic discriminant analysis. The best discrimination was achieved with BAP, closely followed by ICTP. BAP and ICTP together gave a slight improvement over the use of the two markers separately. However, even in this case the degree of discrimination was poor and its clinical utility was limited. In fact, to achieve a specificity of 95%, the sensitivity of the test was about 20%; conversely, with a sensitivity of 95%, the specificity was below 10%. In conclusion, based on our findings, we believe that blood levels of the investigated markers cannot replace bone scintigraphy in the follow-up of breast cancer patients for the early detection of bone metastases. Received 14 April and in revised form 5 July 1997     

早期肠道营养对烧伤后肠源性高代谢的影响

从８０年代末起，通过对６００只大（豚）鼠、６０只兔和６０头小香猪所建立的４种烧伤后早期营养的动物模型，以及２１例严重烧伤病人对比分析，发现烧伤后早期肠道喂养可改善胃肠道血流供应，减轻肠道缺血再灌流损伤；可维护肠粘膜结构以及吸收、分泌、运动功能，降低门脉、中心静脉血内毒素水平，减少肠道内毒素易位；可降低伤后枯否细胞获得数、吞噬墨汁枯否细胞数和面积，以及其培养上清中肿瘤坏死因子（ＴＮＦ）量，对伤后枯否细胞的活化有刺激作用；可降低血胰高糖素、皮质醇、儿茶酚胺、ＴＮＦ、ＩＬ－８前列腺素Ｅ２（ＰＧＥ２）等递质的水平，降低高代谢，使烧伤４５％成人静息能量消耗（ＲＥＥ）在烧伤后４、８、１４ｄ的均值降低２８．６％。通过相关分析发现ＲＥＥ与血丙二醛（ＭＤＡ）、内毒素、分解激素、ＴＮＦ均呈显著正相关（ｒ＝０．７３８６～０．９９２２，Ｐ＜０．０５～０．０１）。     

Effect of prior exercise in Pi/PC ratio and intracellular pH during a standardized exercise. A study on human muscle using [31P]NMR

Seven subjects underwent a standard localized exercise of calf muscles in order to investigate whether the metabolic exercise-induced steady-state, as revealed by the evaluation of inorganic phosphate/phosphocreatine ratio, depends on the conditioning of the muscle just prior to the exercise. The experimental protocols consisted of two separate experiments using first [³¹P]nuclear magnetic resonance spectroscopy and second (on 3 subjects) infrared oxyphotometry to respectively follow variation of energy metabolism and tissular deoxygenation. The exercise consisted of 240 successive plantar flexions (0.5 Hz frequency) against a high load equivalent to SO% of the maximal voluntary contraction. This exercise was accomplished before cold exercise and after warm exercise, a warming-up period bringing to approximately 50% of Vo_2max. The results showed that: (1) steady-state level of phosphate/phosphocreatine and intracellular acidosis was significantly lowered by warming-up; (2) cold and warm exercise steady-state of calculated adenosine diphosphate values were not significantly different; (3) cold exercise rapidly induced a high tissular deoxygenation that is not observed during warm exercise; and (4) time-constant of phosphocreatine resynthesis is lowered after warm exercise but the initial slope of time-evolution is not modified. Parallel experiments also showed that phosphate/phosphocreatine steady-state was not modified in comparison with warm exercise when the same power of exercise was reached by stepwise incrementation of the charge. From these results we postulate that a better tissue oxygenation due to a global or localized warming-up allows to reach the same mechanical performance with a lower decrease of PCr content, owing to a faster adjustment of oxidative metabolism during the transitional period. However the aerobic pathway flux during the steady-state is probably the same before and after the warming-up despite different values of phosphate/phosphocreatine. As a consequence it can be assumed that this ratio is not a good indicator of the rate of muscle oxidative metabolism during the steady-state phase of the exercise.     

比较异丙酚和依托咪酯对心脏瓣膜置换术患者过氧化脂质和超氧化物歧化酶的影响

目的:观察异丙酚对心脏瓣膜置换术患者过氧化脂质和超氧化物歧化酶的影响。方法:20例瓣膜置换术患者分为异丙酚组和依托咪酯组。分别在心肌缺血再灌注前后取血做过氧化脂质和超氧化物歧化酶测定,同时记录心电图和平均动脉压。结果:过氧化脂质在异丙酚组主动脉插管时下降,主动脉开放后升高,均有显著差异(P<0.05,P<0.01)。依托咪酯组主动脉开放后明显升高,亦高于异丙酚组同时值,差异均显著(P<0.01)。超氧化物歧化酶主动脉开放后两组均下降(P<0.05,P<0.01),两组间无差异。主动脉开放后心律失常、心肌缺血、电击复跳例数异丙酚组少于依托咪酯组。结论:异丙酚可明显降低心肌缺血再灌注后过氧化脂质含量,减少心律失常和心肌缺血现象。     

煤石英对大鼠肺泡巨噬细胞氧化系统的影响

利用染煤石英混合粉尘大鼠作为实验模型，研究在实验性大鼠煤矽肺形成过程中肺泡巨噬细胞氧化和抗氧化系统的改变。结果表明在染煤石英粉尘７天，脂质过氧化产物有轻度升高，至３０天时己恢复正常，超氧化物歧化酶在染尘后７天降低，以后恢复至正常，而还原型谷胱甘肽和谷胱甘肽过氧化物酶升高明显，这与石英所致肺泡巨噬细胞的变化明显不同，说明脂质过氧化反应在煤矽肺形成过程中作用不明显。