Human cytochrome P-450 metabolism of retinals to retinoic acids.

Retinoic acids have important pleiotropic biological effects and thus the potential for human cytochrome P-450s (CYPs) to mediate retinoic acid synthesis was investigated. We examined the retinoic acid synthetic activity of human cDNA-expressed CYP1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4, 3A4+ cytochrome b(5) (b(5)), 3A5, and 4A11, expressed individually in insect cells together with NADPH-P-450 reductase. Only CYP1A1, 1A2, 1B1, and 3A4+b(5) converted all-trans-retinal (20 microM) to all-trans-retinoic acid with turnover numbers of 0.

Induction of rat small intestinal cytochrome P-450 2J4.

Cytochrome P-450 (CYP) 2J4 is a member of the recently identified CYP2J subfamily-part of the CYP superfamily-and is primarily expressed in rat small intestinal epithelium (enterocytes). Studies to determine small intestinal CYP2J4 inducibility by prototypic CYP inducers have been undertaken. Immunoblot analysis of enterocyte microsomes from rats treated with beta-naphthoflavone, dexamethasone, or phenobarbital revealed unchanged, diminished, or slightly increased levels of CYP2J4 protein, respectively, relative to vehicle-treated rats, whereas rats treated with pyrazole (200 mg/kg) had 3- to 4-fold increased levels of CYP2J4.

The effects of blood lactate concentration on perception of effort during graded and steady state treadmill exercise.

Studies have reported that ratings of perceived exertion (RPE) are a valid tool for exercise prescription when blood lactate concentration (BLC) is used as the intensity criterion. However, few have studied the relationship between RPE and BLC during commonly used graded exercise tests (GXTs) and simulated exercise training. The purpose of this study was to determine if the RPE: BLC relationship is transferable across GXTs and a steady state exercise trial (SST).

Characterization of human small intestinal cytochromes P-450.

Human small intestine epithelial cells (enterocytes) provide the first site for cytochrome P-450 (CYP)-catalyzed metabolism of orally ingested xenobiotics. The CYP composition of enterocytes could thus affect the potential toxicity or therapeutic efficacy of xenobiotics by modifying systemic uptake. We have characterized human enterocyte CYP composition to enable assessment of its functional roles.

Biotransformation of coumarin by rodent and human cytochromes P-450: metabolic basis of tissue-selective toxicity in olfactory mucosa of rats and mice.

Coumarin was previously found to cause tissue-selective toxicity in the olfactory mucosa (OM) of rats and mice, with rats being the more sensitive species. The aim of this study was to explore the role of target tissue biotransformation in OM-selective toxicity and the metabolic basis of the species differences in coumarin toxicity. At least six coumarin metabolites were detected in OM microsomal reactions, with o-hydroxyphenylacetaldehyde (o-HPA) being the most abundant.

Evaluation of a new standardized ramp protocol: the BSU/Bruce Ramp protocol.

Background: Because of recent technological advances, exercise testing laboratories now have the ability to use ramp protocols with treadmill exercise tests. Since the Bruce protocol is the most widely used treadmill protocol in clinical laboratories, a standardized ramp treadmill protocol was developed that corresponds to the speed and grade settings of the Bruce protocol at each 3-minute time interval. The purpose of this study was to evaluate the utility of using subject demographic and exercise test data to predict peak oxygen uptake (VO2peak) for tests conducted with the BSU/Bruce Ramp protocol.

The effect of exercise training on the severity and duration of a viral upper respiratory illness.

Purpose: The purpose of this investigation was to determine whether exercise training affects the severity and duration of a rhinovirus-caused upper respiratory illness (URI).

Methods: Subjects who were rhinovirus 16 (RV 16) antibody-free completed a graded exercise test. Thirty-four individuals (ages 18-29 yr) of moderate fitness (32 mL.

Caffeine based measures of CYP1A2 activity correlate with oral clearance of tacrine in patients with Alzheimer's disease.

Aims: To study the potential utility of caffeine based probes of CYP1A2 enzyme activity in predicting the pharmokinetics of tacrine in patients with Alzheimer's disease.

Methods: The pharmokinetics of a single 40 mg oral dose of tacrine were measured in 19 patients with Alzheimer's disease. Each patient also received 2 mg kg(-1) [13C-3-methyl] caffeine orally and had breath and urine samples collected.

16Alpha-hydroxylation of estrone by human cytochrome P4503A4/5.

The cytochrome P450 (P450) enzymes that catalyse metabolism of the estrogen, estrone (E1), to the putative carcinogen 16alpha-hydroxy E1 (16alpha-OHE1) in humans were determined. The potential of the most abundant circulating form of estrogen, estrone 3-sulfate (E1S), to be the substrate was also investigated. Human liver microsomal sulfatases convert E1S to E1, an essential prerequisite for formation of 16alpha-OHE1 from added E1S in this system.

Caffeine consumption habits do not influence the exercise blood pressure response following caffeine ingestion.

Background: The purpose of this study was to determine if the BP response during walking following caffeine ingestion differed between those who regularly consume caffeine and those who do not.

Methods: A double-blind cross-over experimental design was used. Data were collected in a research laboratory with a clinical exercise testing room.

Characterization of the cytochrome P450 CYP2J4: expression in rat small intestine and role in retinoic acid biotransformation from retinal.

The sites of expression in the small intestine and the function of CYP2J4, a recently identified rat cytochrome (P450) isoform found to be predominantly expressed in the small intestine, were characterized. Immunoblot analysis with a polyclonal antibody to heterologously expressed CYP2J4 revealed that expression of CYP2J4 was at the highest level in the distal duodenum and jejunum and decreased toward the ileum. Villous cells expressed higher levels of CYP2J4 than crypt cells.

Warfarin analog inhibition of human CYP2C9-catalyzed S-warfarin 7-hydroxylation.

Human metabolism of the S-warfarin enantiomer is catalyzed primarily by cytochrome P4502C9 (CYP2C9), which, because of the enzyme's broad drug substrate specificity, leads to drug-S-warfarin interactions. Several warfarin analogs have been synthesized and used to determine whether they exhibit diminished interactions with CYP2C9. The kinetics of the warfarin analogs' inhibition of human liver microsomal CYP2C9 catalyzed metabolism of S-warfarin to S-7-hydroxywarfarin have been investigated.

Inhibition of estrone sulfatase in human liver microsomes by quercetin and other flavonoids.

Inhibition of estrone sulfatase activity offers the potential for breast cancer prevention therapy by blocking a route to estrogen synthesis. We have investigated the inhibition of this activity by natural flavonoids in a human hepatic microsomal preparation in vitro. The majority of studies were performed with a male liver, but male and female livers exhibited comparable estrone sulfatase activities.

Evaluation of lipid profile measurements obtained from the Cholestech L.D.X analyzer.

Background: The Cholestech L.D.X analyzer has the capability of performing a lipid profile in approximately 5 minutes.

Self-directed work teams: an 18-month review.

Visionaries are individuals who imagine how the ideal practice should be setup. Realists view practices the way they are actually setup. To bring these individuals together toward a common goal is what self-directed work teams can provide your practice.

Validity of rating of perceived exertion during graded exercise testing in apparently healthy adults and cardiac patients.

Purpose: Recent exercise guidelines recommend a generalized rating of perceived exertion (RPE) range of 12 to 16 (15-point Borg scale) as the perceptual range associated with a physiological training effect. However, whether an individual who selects an RPE within the generalized range during an graded exercise test or exercise training, is actually within the correlated physiological range (50 to 85% maximum oxygen consumption [VO2max]) has not been studied in large samples of apparently healthy individuals or cardiac patients. The purpose of the present study was to assess the validity of the generalized RPE recommendations in a large heterogeneous group of apparently healthy subjects and cardiac patients.

The molecular epidemiology of lung cancer.

One in ten tobacco smokers develops bronchogenic carcinoma over a lifetime. The study of susceptibility of an individual and a population to lung cancer traditionally has been limited to the study of tobacco smoke dose and family history of cancer. New insights into lung carcinogenesis have made the study of molecular markers of risk possible in human populations in the emerging field of molecular epidemiology.

Alternative splicing of CYP2D mRNA in human breast tissue.

The human cytochrome P450 (CYP) 2D subfamily comprises the CYP2D6 gene and four pseudogenes, CYP2D7P1 and 2 and CYP2D8P1 and 2. The CYP2D6 gene product is a prominent drug-metabolizing enzyme, which is probably constitutive and has no known inducing agents. Alternative splicing of the pre-mRNAs of these genes has been detected in human liver and breast tissue.

Comparisons of CYP2D messenger RNA splice variant profiles in human lung tumors and normal tissues.

Allelic variants of the CYP2D6 gene, a member of the cytochrome P450 gene superfamily, have been implicated in susceptibility to lung carcinogenesis. Human breast CYP2D6 and CYP2D7P (from a pseudogene) mRNAs were previously reported to be expressed as a series of splice variants. In this study, the expression of full-length and splice variants of these mRNAs in human lung tissue and tumors are reported for the first time and are compared in order to probe the potential for differential CYP2D6 regulation in lung normal tissue and tumors.

Effect of a rhinovirus-caused upper respiratory illness on pulmonary function test and exercise responses.

Upper respiratory illness (URI) may cause more frequent acute disability among athletes than all other diseases combined. The purposes of this study were to determine the impact of a rhinovirus-caused URI on resting pulmonary function submaximal exercise responses and on maximal exercise functional capacity. Twenty-four men and 21 women (18-29 yr) of varying fitness levels were assigned to the experimental group (URI), and 10 additional individuals served as a control group (CRL).

Induction of CYP1A1 by beta-naphthoflavone in IEC-18 rat intestinal epithelial cells and potentiation of induction by dibutyryl cAMP.

We have examined the inducibility of CYP1A1 by beta-naphthoflavone (BNF) in a rat intestinal epithelial cell line, IEC-18, and the associated interaction between cAMP and BNF. CYP1A1 was not constitutively expressed in IEC-18 cells. Upon treatment with BNF, CYP1A1 RNA, protein, and microsomal 7-ethoxyresorufin O-deethylase activity were detected.

CDNA cloning, heterologous expression, and characterization of rat intestinal CYP2J4.

The small intestine is the major portal of entry of ingested xenobiotics. Previous studies from this and other laboratories indicated that at least 6 of the 33 xenobiotic metabolizing forms of P450 currently identified are expressed in rat small intestinal epithelial cells. In the present study, a previously unidentified rat P450, designated CYP2J4, was identified in rat small intestine using PCR.

Reliability of perceived exertion during graded exercise testing in apparently healthy adults.

Purpose: Ratings of perceived exertion (RPE) are widely used for monitoring individuals during graded exercise testing. Studies of the reliability of RPEs across various exercise conditions have produced mixed results. The purpose of this study was to assess the reliability of RPEs during graded exercise testing by comparing the perceptual-physiological relationship between the Bruce and Balke treadmill protocols throughout a broad range of relative exercise intensities.

Human P450 metabolism of warfarin.

The anticoagulant drug warfarin occurs as a pair of enantiomers that are differentially metabolized by human cytochromes P450 (CYP). R-warfarin is metabolized primarily by CYP1A2 to 6- and 8-hydroxywarfarin, by CYP3A4 to 10-hydroxywarfarin, and by carbonyl reductases to diastereoisomeric alcohols. S-warfarin is metabolized primarily by CYP2C9 to 7-hydroxywarfarin.