Regioselective hydroxylation of steroid hormones by human cytochromes P450

This article reviews in vitro metabolic activities [including Michaelis constants (K_m), maximal velocities (V_max) and V_max/K_m] and drug–steroid interactions [such as induction and cooperativity (activation)] of cytochromes P450 (P450 or CYP) in human tissues, including liver and adrenal gland, for 14 kinds of endogenous steroid compounds, including allopregnanolone, cholesterol, cortisol, cortisone, dehydroepiandrosterone, estradiol, estrone, pregnenolone, progesterone, testosterone and bile acids (cholic acid). First, we considered the drug-metabolizing P450s. 6β-Hydroxylation of many steroids, including cortisol, cortisone, progesterone and testosterone, was catalyzed primarily by CYP3A4. CYP1A2 and CYP3A4, respectively, are likely the major hepatic enzymes responsible for 2-/4-hydroxylation and 16α-hydroxylation of estradiol and estrone, steroids that can contribute to breast cancer risk. In contrast, CYP1A1 and CYP1B1 predominantly metabolized estrone and estradiol to 2- and 4-catechol estrogens, which are endogenous ultimate carcinogens if formed in the breast. Some metabolic activities of CYP3A4, including dehydroepiandrosterone 7β-/16α-hydroxylation, estrone 2-hydroxylation and testosterone 6β-hydroxylation, were higher than those for polymorphically expressed CYP3A5. Next, we considered typical steroidogenic P450s. CYP17A1, CYP19A1 and CYP27A1 catalyzed steroid synthesis, including hydroxylation at 17α, 19 and 27 positions, respectively. However, it was difficult to predict which hepatic drug-metabolizing P450 or steroidogenic P450 will be mainly responsible for metabolizing each steroid hormone in vivo based on these results. Further research is required on the metabolism of steroid hormones by various P450s and on prediction of their relative contributions to in vivo metabolism. The findings collected here provide fundamental and useful information on the metabolism of steroid compounds.     

Prognostic significance of time-delay to peak creatine kinase after direct percutaneous coronary intervention in acute myocardial infarction patients

The aim of the present study was to investigate the prognostic significance of time-delay to peak creatine kinase (CK) after successful direct percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI). Our 240 consecutive first AMI attack subjects admitted within 5 hours from onset were successfully reperfused by direct PCI therapy. Subjects were divided into two groups according to the upper quartile value of peak-CK time from onset, the early peak-CK group (peak-CK time < or = 16 hours from onset, n = 180) and the late peak-CK group (peak-CK time > 16 hours, n = 60). (I) The early ST-segment resolution rate was lower in the late peak-CK group compared with the early peak-CK group (P < 0.05), and there were significantly fewer patients with preinfarction angina pectoris in the late peak-CK group than in the early peak-CK group (P < 0.01). (II) LVEF in the chronic stage was significantly lower in the late peak-CK group than in the early peak-CK group (49 +/- 13% versus 57 +/- 13%, P < 0.001). (III) There were significantly more patients with major complications in the late peak-CK group than in the early peak-CK group (required CABG: 10% versus 3%, P < 0.05; cardiac death: 18% versus 3%, P = 0.0001). (IV) Multivariate analysis identified late peak-CK as an independent predictor of cardiac death (Odds ratio 7.91, 95% C.I. 1.40-44.11, P < 0.05). In patients with AMI, the time-delay to peak-CK after successful direct PCI may be closely related to left-ventricular systolic dysfunction and poor patient outcome, including mortality.     

Perforin defects of primary haemophagocytic lymphohistiocytosis in Japan

The perforin gene was analysed in 15 Japanese patients with primary haemophagocytic lymphohistiocytosis (HLH). Perforin gene defects were found in two out of eight patients with familial HLH (FHL), and one out of seven without affected siblings. Four novel mutations were identified. Compound heterozygous mutations (one FHL and one sporadic HLH) and only one allele mutation (one FHL) were defined. Flow cytometry revealed no perforin expression in CD8+ or CD56+ cells from a surviving patient with a mutation. The frequency of mutation was at least 20% of FHL in Japan. Flow cytometry for intracellular perforin may be useful for the screening of FHL2.     

CD30-positive lymphoma in human T-cell leukaemia virus type 1 carrier without monoclonal integration of HTLV-1

Summary. CD30, Ki-1 antigen, an activated T-cell antigen, is a member of the nerve growth factor receptor family. This antigen is expressed on the lymphoma cells of some adult T-cell leukaemia/lymphoma (ATL/L) patients and some patients with Epstein-Barr virus infection. CD30-positive large cell cutaneous T-cell lymphomas occasionally integrate a defective HTLV-1 provirus. We describe here an HTLV-1 carrier who developed Ki-1 lymphoma with no evidence of monoclonal integration of the HTLV-1 proviral sequence.     

Three cases of non-specific interstitial pneumonia associated with primary lung cancer

NSIP associated with primary lung cancer has been rarely reported. In the present report, three cases of histologically proven non-specific interstitial pneumonia (NSIP) associated with primary lung cancer are described. Importantly, in our 3 cases, interstitial pneumonia which is histologically proven to be NSIP was observed diffusely in both lungs. NSIP in these 3 cases responded to steroid therapy. However, 2 patients died from primary lung cancer and 1 patient died from progression of the interstitial pneumonia. Although the association between lung cancer and NSIP has been rarely documented, this combination was considered to be one of the paraneoplastic phenomena. The possible association between primary lung cancer and NSIP is discussed.     

Inflammatory pseudotumor of the liver: Radiologic diagnosis

To determine the characteristic radiologic findings of inflammatory pseudotumor of the liver, various imagings of ten patients (11 lesions) with proven diagnoses of inflammatory pseudotumor were reviewed. Radiologic examinations, i.e., computed tomography (CT; 11 lesions), ultrasonography (11 lesions), magnetic resonance imaging (MRI; 6 lesions), angiography (10 lesions), CT during arterio-portography (CTAP; 3 lesions), and gallium-67 scans (9 lesions) were analyzed for their utility in diagnosis. No inflammatory pseudotumor showed a fibrous capsule around the lesion. Ten of the 11 lesions were poorly demarcated on most of the imagings, and all 11 lesions showed delayed and/or prolonged enhancement on CT or MRI. Arterio-portal shunting was observed in 4 lesions after contrast material administration on CT or angiography. Central lesions with suspiciously high fibrotic tissue content were demonstrated in 5 lesions on CT or MRI. Major vessels coursing in the lesions were demonstrated in 4 lesions by CT, MRI, and CTAP. Inflammatory pseudotumor of the liver should be included in the differential diagnosis in patients with hepatic masses, even if the patients are asymptomatic. If radiologic examinations suggest inflammatory pseudotumor, percutaneous biopsies should be performed so that unnecessary surgery can be avoided.     

Activation of the renin-angiotensin system and chronic hypoxia of the kidney.

Recent studies emphasize the role of chronic hypoxia in the kidney as a final common pathway to end-stage renal failure (ESRD). Hypoxia of tubular cells leads to apoptosis or epithelial-mesenchymal transdifferentiation, which in turn exacerbates the fibrosis of the kidney with the loss of peritubular capillaries and subsequent chronic hypoxia, setting in train a vicious cycle whose end-point is ESRD. While fibrotic kidneys in an advanced stage of renal disease are devoid of peritubular capillary blood supply and oxygenation to the corresponding region, imbalances in vasoactive substances can cause chronic hypoxia even in the early phase of kidney disease. Among various vasoactive substances, local activation of the renin-angiotensin system (RAS) is particularly important because it can lead to the constriction of efferent arterioles, hypoperfusion of postglomerular peritubular capillaries, and subsequent hypoxia of the tubulointerstitium in the downstream compartment. In addition, angiotensin II induces oxidative stress via the activation of NADPH oxidase. Oxidative stress damages endothelial cells directly, causing the loss of peritubular capillaries, and also results in relative hypoxia due to inefficient cellular respiration. Thus, angiotensin II induces renal hypoxia via both hemodynamic and nonhemodynamic mechanisms. In the past two decades, considerable gains have been realized in retarding the progression of chronic kidney disease by emphasizing blood pressure control and blockade of the RAS. Chronic hypoxia in the kidney is an ideal therapeutic target, and the beneficial effects of blockade of RAS in kidney disease are, at least in part, mediated by the amelioration of local hypoxia. (Hypertens Res 2008; 31: 175-184).     

Paradoxical mineralocorticoid receptor activation and left ventricular diastolic dysfunction under high oxidative stress conditions

BACKGROUND: Salt status plays a pivotal role in angiotensin-II-induced organ damage by regulating reactive oxygen species status, and it is reported that reactive oxygen species activate mineralocorticoid receptors. METHOD: To clarify the role of reactive oxygen species-related mineralocorticoid receptor activation in angiotensin-II-induced cardiac dysfunction, we examined the effect of the following: salt status; an MR antagonist, eplerenone; and an antioxidant, tempol in angiotensin-II-loaded Sprague-Dawley rats. RESULTS: Angiotensin-II/salt-loading elevated blood pressure, and neither eplerenone nor tempol antagonized the rise in blood pressure significantly. Left ventricular diastolic function was monitored by measuring peak velocity of a mitral early inflow (E), the ratio of mitral early inflow to atrial contraction related flow (E/A), deceleration time of mitral early inflow and -dP/dt, the time constant (T), and filling pressure (left ventricular end-diastolic pressure) by echocardiography or cardiac catheterization. Despite the suppressed serum aldosterone, left ventricular diastolic function was deteriorated with angiotensin II/high salt, but not affected by angiotensin II/low salt. However, angiotensin-II/salt-induced cardiac dysfunction was restored by eplerenone and tempol. Nicotinamide adenine dinucleotide phosphateoxidase-derived superoxide formation was greater in the hearts of the angiotensin II/high-salt rats than of the angiotensin II/low-salt rats. The expression of the Na(+) -H(+) exchanger isoform 1, a target of mineralocorticoid receptor activation, was significantly increased in the angiotensin II/high-salt group. Both tempol and eplerenone inhibited the angiotensin-II/salt-induced upregulation of Na(+) -H(+) exchanger isoform 1. CONCLUSION: These findings demonstrate that mineralocorticoid receptor activation by oxidative stress can cause left ventricular diastolic dysfunction in a rat model of mild hypertension.     

Radioimmunoassay and immunological properties of eel calcitonin

The immunological properties of eel calcitonin (CT) were studied by checking the cross-reactivities of eel CT or antisera to eel CT to various CT or antisera to these CT. Antisera to eel CT, raised in guinea pig, did not crossreact with either synthetic salmon, porcine or human CT. The antisera to salmon CT weakly crossreacted with eel CT, whereas eel CT did not crossreact with either antisera to porcine or human CT.     

Liver metastasis of rectal cancer with intraluminal growth in the extrahepatic bile duct

Metastatic liver tumors are considered to have a tendency for expansive growth and rarely invade the bile duct. We recently encountered a resected case of liver metastasis from rectal cancer with intraluminal growth in the extrahepatic bile duct with a successful left trisegmentectomy of the liver. A 54-year-old woman underwent a posterior total pelvic exenteration for advanced rectal cancer. Ultrasonography and computed tomography four months after the first operation demonstrated a solitary occupied lesion in the liver with dilation of the left hepatic duct. Endoscopic retrograde cholangiopancreatography disclosed a filling defect in the intra- to extrahepatic bile duct. Liver metastasis from rectal cancer with intraluminal growth in the bile duct was suspected despite a consideration of primary bile duct cancer. A left trisegmentectomy of the liver and resection of the extrahepatic bile duct with a right hepatojejunostomy were performed. The tumor had invaded the intrahepatic bile duct and had developed intraluminally in the extrahepatic bile duct. Tumor thrombi were microscopically found in the bile duct of the left caudal lobe. Liver metastasis arising from colorectal cancer with intraluminal growth in the bile duct is rare, however we encountered such a case with a successful resection involving a left trisegmentectomy of the liver.