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C J Henderson

Publications and source records attributed to C J Henderson.

At least 37 records · Page 2Linked to original sources
PubMed1998

Increased skin tumorigenesis in mice lacking pi class glutathione S-transferases.

The activity of chemical carcinogens is a complex balance between metabolic activation by cytochrome P450 monooxygenases and detoxification by enzymes such as glutathione S-transferase (GST). Regulation of these proteins may have profound effects on carcinogenic activity, although it has proved impossible to ascribe the observed effects to the activity of a single protein. GstP appears to play a very important role in carcinogenesis, although the precise nature of its involvement is unclear. We have deleted the murine GstP gene cluster and established the effects on skin tumorigenesis induced by the polycyclic aromatic hydrocarbon 7, 12-dimethylbenz anthracene and the tumor promoting agent 12-O-tetradecanoylphorbol-13-acetate. After 20 weeks, a highly significant increase in the number of papillomas was found in the GstP1/P2 null mice [GstP1/P2(-/-) mice, 179 papillomas, mean 9.94 per animal vs. GstP1/P2(+/+) mice, 55 papillomas, mean 2.89 per animal, (P < 0.001)]. This difference in tumor incidence provides direct evidence that a single gene involved in drug metabolism can have a profound effect on tumorigenicity, and demonstrates that GstP may be an important determinant in cancer susceptibility, particularly in diseases where exposure to polycyclic aromatic hydrocarbons is involved, for instance in cigarette smoke-induced lung cancer.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1998

Pi-class glutathione S-transferase: regulation and function.

Our laboratory has been involved in the study of Glutathione S-transferase pi (GST pi) for many years, both in terms of regulation of gene expression and in trying to understand the endogenous function(s) of this enzyme and also what role it may play in the carcinogenic process [1]. Over-expression of GST pi has been associated with carcinogenesis and the development of many different human tumours, for example testis [2], ovarian [3] and colorectal [4] and is often inversely correlated with prognosis or patient survival [5,6]. In addition, GST Pi has been implicated in the acquisition of antineoplastic drug resistance [7-9]. In order to study the transcriptional regulation of this gene, we have utilised a multi-drug resistant derivative (VCREMS) of the human mammary carcinoma cell line, MCF7, in which GST P1 mRNA and protein are significantly elevated in the absence of gene amplification [10-13]. Interestingly, we have recently reported the discovery of polymorphisms at the GSTP1 locus, resulting in two alleles GSTP1a and GSTP1b. In the study, the GSTP1b allele was found with increased frequency in bladder and testicular cancer, while the GSTP1a allele was significantly decreased in cases of prostate cancer [14]. In an attempt to elucidate the endogenous role(s) of GST pi, we have used homologous recombination in embryonic stem (ES) cells to inactivate both murine GST Pi genes and create a mouse strain completely deficient in the expression of this enzyme. This provides us with a unique animal model with which to study the effects of the absence of GST pi expression on the metabolism and pharmacokinetics of xenobiotics.

Alleles↗
PubMed1998

The offset of beta-adrenoceptor antagonism of the responses of the rat right ventricle to isoprenaline.

1. The aim of the study was to test the hypothesis that the offset of action of beta-adrenoceptor antagonists on the heart is related to their lipophilicity, with low and highly lipophilic drugs having a rapid and slow offset, respectively. The effects of beta-blockers with low (atenolol), moderate (celiprolol), high (propranolol) and very high (bopindolol) lipophilicity on the contractile responses of the rat right ventricle to isoprenaline were determined. 2. Atenolol at 10(-6) and 10(-5) M, celiprolol at 10(-7), 10(-6) and 10(-5) M, propranolol at 10(-8), 10(-7) and 10(-6) M and bopindolol at 2 x 10(-9) and 10(-8) M caused parallel rightward shifts of the isoprenaline response curves with no effect on maximum responses. The Schild plots for atenolol, celiprolol and propranolol had slopes that were not significantly different from 1, which is indicative of competitive reversible antagonism. The pKB values were 7.33, 7.78, and 8.79 for atenolol, celiprolol, and propranolol, respectively. The Schild plot for bopindolol had a slope that was significantly greater than 1. 3. Our hypothesis is supported as the effects of propranolol and bopindolol were more slowly offset than those of atenolol and celiprolol. Thus, the concentration-ratio of 141 in the presence of atenolol at 10(-5) M was reduced to 4 after the first wash, whereas the ratio of 100 in the presence of propranolol at 10(-7) M was only reduced to 45 after a similar wash. The ratio of 54 with celiprolol at 10(-6) M was reduced to 5, whereas the ratio of 70 with bopindolol at 10(-8) M was only reduced to 28 by the first wash. 4. The effects of bopindolol were very slowly or not reversible over two washes in the absence or presence of atenolol at 10(-6) M. It is suggested that bopindolol is a very slowly reversible beta-blocker, and that this contributes to its slow offset of action.

Adrenergic beta-Antagonists↗
PubMed1998

Monte Carlo modelling of an extended DXA technique.

The precision achieved in measuring bone mineral density (BMD) by commercial dual-energy x-ray absorptiometry (DXA) machines is typically better than 1%, but accuracy is considerably worse. Errors, due to inhomogeneous distributions of fat, of up to 10% have been reported. These errors arise because the DXA technique assumes a two-component model for the human body, i.e. bone mineral and soft tissue. This paper describes an extended DXA technique that uses a three-component model of human tissue and significantly reduces errors due to inhomogeneous fat distribution. In addition to two x-ray transmission measurements, a measurement of the path length of the x-ray beam within the patient is required. This provides a third equation, i.e. T = ts + tb + tf where T, ts, tb and tf are the total, lean soft tissue, bone mineral and fatty tissue thicknesses respectively. Monte Carlo modelling was undertaken to make a comparison of the standard and extended DXA techniques in the presence of inhomogeneous fat distribution. Two geometries of varying complexity were simulated. In each case the extended DXA technique produced BMD measurements that were independent of soft tissue composition whereas the standard technique produced BMD measurements that were strongly dependent on soft tissue composition. For example, in one case, the gradients of the plots of BMD versus fractional fat content were for standard DXA (-0.183+/-0.037) g cm(-2) and for extended DXA (0.027+/-0.044) g cm(-2). In all cases the extended DXA method produced more accurate but less precise results than the standard DXA technique.

Absorptiometry, Photon↗
PubMed1998

Use of transgenic animals in understanding molecular mechanisms of toxicity.

Understanding molecular mechanisms of chemical toxicity and the potential risks of drugs to man is a pivotal part of the drug development process. With the dramatic increase in the number of new chemical entities arising from high throughput screening, there is an urgent need to develop systems for the rapid evaluation of potential drugs so that those agents which are most likely to be free of adverse effects can be identified at the earliest possible stage in drug development. The complex mechanisms of action of chemical toxins has made it extremely difficult to evaluate the precise toxic mechanism and also the relative role of specific genes in either potentiating or ameliorating the toxic effect. This problem can be addressed by the application of genetic strategies. Such strategies can exploit strain differences in susceptibility to specific toxic agents or, with the rapidly developing technologies, can exploit the use of transgenic animals where specific genes can be manipulated and subsequent effects on chemical toxicity evaluated. Transgenic animals can be exploited in a variety of ways to understand mechanisms of chemical toxicity. For example, a human gene encoding a drug metabolizing enzyme can be directly introduced and the effects on toxic response evaluated. Alternatively, specific genes can be deleted from the mouse genome and the consequences on toxicological response determined. Many toxic chemical agents modulate patterns of gene expression within target cells. This can be used to screen for responses to different types of toxic insult. In such experiments the promotor of a stress-regulated gene can be ligated to a suitable reporter gene, such as lacZ, or green fluorescent protein, and inserted into the genome of an appropriate test species. On administration of a chemical agent, cells which are sensitive to the toxic effects of that chemical will express the reporter, which can then be identified using an appropriate assay system. This latter strategy provides the potential for screening a large number of compounds rapidly for their potential toxic effects and also provides information on tissue and cellular specificity. Experiments using transgenic animals can be complex, and care must be taken to ensure that the results are not affected by background activities within the species being used. For example, the introduction of a specific human cytochrome P450 gene may have no effect on the metabolic disposition of a drug or toxin because of the background activity within the mouse. As the toxicity of a chemical agent is determined by a wide range of different factors including drug uptake, metabolism, detoxification and repair, differences between man and the species being used could potentially generate a toxic response in the animal model whereas no toxicity may be observed in man. In spite of these confounding factors, the application of transgenic animals to toxicological issues has enormous potential for speeding up the drug discovery process and will undoubtedly become part of this process in the future.

Animals↗
PubMed1997

A general strategy for the expression of recombinant human cytochrome P450s in Escherichia coli using bacterial signal peptides: expression of CYP3A4, CYP2A6, and CYP2E1.

Heterologous expression of unmodified recombinant human cytochrome P450 enzymes (P450s) in Escherichia coli has proved to be extremely difficult. To date, high-level expression has only been achieved after altering the 5'-end of the native cDNA, resulting in amino acid changes within the P450 protein chain. We have devised a strategy whereby unmodified P450s can be expressed to high levels in E. coli, by making NH2-terminal translational fusions to bacterial leader sequences. Using this approach, we initially tested two leader sequences, pelB and ompA, fused to CYP3A4. These were compared with an expression construct producing a conventional NH2-terminally modified CYP3A4 (17alpha-3A4). Both leader constructs produced spectrally active, functional protein. Furthermore, the ompA-3A4 fusion gave higher levels of expression, and a marked improvement in the recovery of active P450 in bacterial membrane fractions, when compared with 17alpha-3A4. We then tested the ompA leader with CYP2A6 and CYP2E1, again comparing with the conventional (17alpha-) approach. As before, the leader construct produced active enzyme, and, for CYP2E1 at least, gave a higher level of expression than the 17alpha-construct. The ompA fusion strategy thus appears to represent a significant advance for the expression of P450s in E. coli, circumventing the previous need for individual optimization of P450 sequences for expression.

Aminolevulinic Acid↗
PubMed1997

Predictors of total body bone mineral density in non-corticosteroid-treated prepubertal children with juvenile rheumatoid arthritis.

OBJECTIVE: To determine the extent of significant osteopenia in prepubertal patients with juvenile rheumatoid arthritis (JRA) not treated with corticosteroids and to identify variables that are highly related to bone mineralization in this population. METHODS: In a cross-sectional study, 48 JRA patients and 25 healthy control subjects ages 4.6-11.0 years were evaluated. Total body bone mineral density (TB BMD) was determined by Hologic dual energy x-ray absorptiometry. All patients were prepubertal (Tanner stage I or II) and had never taken corticosteroids. For comparison, JRA patients were divided into "low" TB BMD (Z score < or =-1) or "normal" TB BMD (Z score >-1). RESULTS: The overall mean +/- SD TB BMD scores did not differ between the JRA subjects (0.75 +/- 0.06 gm/cm2) and controls (0.73 +/- 0.07 gm/cm2; P > 0.30). However, 29.2% of the JRA patients had low TB BMD, whereas only 16% would be expected to have low TB BMD based on the standard normal distribution (goodness of fit chi(2) = 4.84, P = 0.01). The mean Z score for the JRA patients with low TB BMD was -1.43, and for those with normal TB BMD, it was 0.32. The JRA subjects with low TB BMD were significantly younger, had more active articular disease, greater physical function limitation, higher erythrocyte sedimentation rate, higher joint count severity score, lower body mass index, lower lean body mass, less participation in organized sports, and more protein and vitamin D in their diet compared with JRA patients with normal TB BMD (all P < 0.05). Using logistic regression, a model including age at JRA onset, Juvenile Arthritis Functional Assessment Report (JAFAR) score, triceps skin-fold percentiles, percentage US recommended daily allowance for dietary magnesium intake, and serum 1,25-dihydroxyvitamin D levels was able to accurately segregate 79.6% of the JRA subjects into either the low or normal TB BMD groups (chi(2) = 20.5, P = 0.001). CONCLUSION: This study demonstrated that in a mildly to moderately ill prepubertal JRA population that had never been exposed to corticosteroids, almost 30% had significantly low TB BMD. The patients with low TB BMD had more active and severe articular disease and greater physical function limitation. Disease-related parameters in JRA appear to exert a negative effect on bone mineralization even in prepubertal children, which can be demonstrated despite the exclusion of corticosteroid-treated patients.

Adrenal Cortex Hormones↗
PubMed1997

The effects of bromoacetylalprenololmenthane on the responses to isoprenaline of the left ventricle from normo-, prehyper- and hypertensive rats.

1. We have studied the effects of bromoacetylalprenololmenthane (BAAM), a very slowly reversible beta-adrenoceptor antagonist, on the responses of the left ventricle of 5 and 22 week old Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs) to isoprenaline. At 5 weeks the SHRs were prehypertensive and at 22 weeks they had hypertension-induced hypertrophy of the left ventricle. 2. The mean potency of isoprenaline on the left ventricle from 5 week old WKY was similar to that obtained on left ventricle with BAAM at 10(-6) M for 30 min, there was a parallel rightward shift of the isoprenaline concentration-response curves. Treatment with a higher concentration of BAAM (10(-5)M) caused non-parallel rightward shifts of the concentration-response curves, with a depression of the isoprenaline maximum responses. These data were used to derive affinity (KA) values for isoprenaline. The mean isoprenaline KA value on the left ventricle from 5 week old WKY was 2.44 x 10(-6)M, and similar KA values were obtained on the left ventricles from 22 week old WKY and 5 and 22 week old SHRs. On all the left ventricles tested, isoprenaline produced a half maximal response by occupying less than 1%, and a near maximal response by occupying about 5% of the available beta(1)-adrenoceptors. 4. This study has shown that there are no differences in the cardiac responses to isoprenaline at beta(1)-adrenoceptors, isoprenaline KA values or the beta(1)-adrenoceptor reserve for isoprenaline on the SHR left ventricle in prehypertension or in the early stages of hypertension-induced hypertrophy.

Adrenergic beta-Agonists↗
PubMed1996

Transfer of PCBs via lactation simultaneously induces the expression of P450 isoenzymes and the protooncogenes c-Ha-ras and c-raf in neonates.

At the first day of lactation, maternal rats were injected with a single i.p. dose of 100 or 250 mg/kg body weight of a mixture of polychlorinated biphenyls (Aroclor 1254). This treatment caused significant increases in both material and neonatal hepatic cytochrome P-450, cytochrome b5, and cytochrome-c-(P-450) reductase. Transfer of PCBs via lactation resulted in significant increases in hepatic enzyme activities catalysed by neonatal CYP1A1, CYP1A2, CYP2B1, CYP3A1, and CYP2E1 using a variety of substrates. In contrast, the metabolism of dimethylnitrosamine and aminopyrine was only marginally (up to 2-fold) increased in maternal animals four days post treatment. Further measurements showed significant increases in maternal and neonatal epoxide hydrolase, glutathione-S-transferase, and UDP-glucuronyl transferase activities, thus suggesting a coordinated response for an induction of CYP1A1, CYP1A2, CYP2A1, CYP2B1, CYP2E1, CYP3A1, and CYP4A1 in both maternal and neonatal CYP2C6, and at the higher dose the expression of neonatal CYP2E1 was significantly reduced. Northern blot analysis provided further evidence for significant increases in maternal and neonatal hepatic CYP1A1, CYP1A2, CYP2B1, and CYP2E1 mRNA, but reduced amounts of CYP2C7 and CYP4A1 mRNA. Additional Northern blot hybridization experiments may suggest an increased expression of the protooncogenes c-Ha-ras and c-raf in the mother and the neonate upon treatment of maternal rats with Aroclor 1254. Lactation itself may result in an increased expression of the latter protooncogenes, but the mRNA of the protooncogenes c-erb A and c-erb B was not detected in any of the tissues examined.

Animals↗
PubMed1996

Modulation of the cytochrome P450 system as a mechanism of chemoprotection.

The cytochrome P450-dependent mono-oxygenase system has evolved as one of our primary defences against toxic chemicals present in our environment. This multi-enzyme system functions as an adaptive response to environmental challenge in that exposure to specific toxic agents induces the expression of cytochrome P450 isozymes active in their metabolism. In most cases, such metabolism leads to an increased rate of chemical detoxification, but in certain cases it can also lead to an increased rate of chemical activation to toxic products. The induction of cytochrome P450s leading to cytoprotection is a major mechanism of chemoprotection, and it is well documented that this pathway prevents a large number of toxic reactions. Incredibly, despite the importance of this metabolic pathway, the effects of a wide range of chemoprotective agents with different mechanisms of action on the expression of specific cytochrome P450 isozymes remains poorly understood. In this chapter, we discess the ability of different chemical compounds to modulate cytochrome P450 both at the transcriptional and post-transcriptional levels, in a way which affects its ability to metabolize or detoxify chemical carcinogens.

Animals↗
PubMed1995

Physical activity in children with juvenile rheumatoid arthritis: quantification and evaluation.

OBJECTIVE: To measure daily physical activity in patients with juvenile rheumatoid arthritis (JRA) and in healthy controls, and to identify variables that may influence physical activity in JRA patients. METHODS: Twenty-three prepubertal children, ages 5-11 years, with mild to moderate JRA and no prior exposure to systemic glucocorticosteroids, were compared to 23 healthy children of similar age. Physical activity was measured for 3 days (minimum of one weekend day) using 3 standardized methods simultaneously. Total body movement was assessed by the Caltrac accelerometer and the University of Cincinnati Motion Sensor (UCMS). The Caltrac measured movement in the vertical plane; the UCMS measured movement of 10 degrees or more from the horizontal plane. The type and intensity of daily physical activity was measured by the 3-day activity record, which also recorded the number of hours of daily sleep. Participation and duration of involvement in organized sports was ascertained by questionnaire. RESULTS: The mean physical activity was significantly lower in JRA patients than in controls for the activity diary (P = 0.05). However, daily body movement measured by the Caltrac and UCMS were similar for both groups. Differences were seen in the number of hours of sleep per day (P = 0.02) and participation in strenuous activities (P < 0.01). JRA patients had significantly less participation in organized sports (P = 0.01). CONCLUSION: There was less daily physical activity by this group of JRA patients than for healthy age- and sex-matched control subjects.

Arthritis, Juvenile↗
PubMed1995

Hand skin temperature variations for work in moderately cold environments and the effectiveness of periodic rewarming.

An investigation of skin surface temperature variations under actual work conditions for four locations on the hand studied the utility of hot water immersion sinks for restoring heat to the hands during exposure to moderately cold temperatures in a food processing plant. Hand skin temperature was recorded for 15 subjects in 2 jobs with an ambient temperature of 13.3 degrees C (56 degrees F) and 1 job with an ambient temperature of 23.9 degrees C (75 degrees F). Averaged over all jobs, the mean temperature for the dorsal and palmar third finger was 17.7 degrees C (63.9 degrees F), which was significantly (p < 0.01) cooler than the mean dorsal and palmar hand temperature of 28.9 degrees C (84.0 degrees F). There was no significant difference between dorsal and palmar temperatures for either the finger or the hand (p > 0.05). In the warm environment there were no significant differences in skin temperature for any of the four hand locations (p > 0.05). An exponential model of digital warming and cooling was empirically derived using 12 subjects for predicting finger skin temperature when periodically rewarming the hands using a hot water immersion sink. The dorsal and palmar finger had a mean time constant of 151 sec for warming during immersion, 640 sec for initial cooling after a 15- to 30-min rest break at room temperature, and 198 sec for cooling after rewarming in the hot sink. The sink did not appreciably raise minimum finger skin temperature after subjects rewarmed the hands for as long as 2 min and then worked for more than 10 min without a rewarming session.

Adult↗
PubMed1995

Divergent regulation of cytochrome P450 enzymes by morphine and pethidine: a neuroendocrine mechanism?

We have studied the effects of opiates on cytochrome P450 (CYP) expression in rats and, intriguingly, found that these compounds have divergent effects on this system. Morphine induced a selective down-regulation of hepatic 16 alpha-hydroxylation of androstenedione, which was associated with a reduction in the expression of the 16 alpha-hydroxylation-associated CYP2C11. In addition, other enzymes from the CYP2C, CYP3A, and CYP4A gene families were also suppressed, whereas CYP1A2, CYP2B1, and CYP2E1 were induced. These changes were reflected in the mRNA levels, indicating that they were due to alterations at the transcriptional level. alpha 2-Adrenoceptor blockade with yohimbine augmented the effects of morphine on proteins identified by antibodies against CYP2C11 and CYP3A, indicating an involvement or influence of the alpha 2-adrenergic receptor system. In contrast, pethidine had completely different effects. No CYPs were suppressed by this compound. CYP1A2, CYP2B1, CYP2C6, CYP2C7, CYP3A, and CYP4A1 were all induced by pethidine treatment, whereas CYP2C11 and CYP2E1 were unchanged. Our results demonstrate for the first time the divergent effects of pethidine and morphine on the hepatic CYP system, indicating that an opioid receptor mechanism is not involved. These differences are probably mediated by different influences on growth hormone secretion. The mechanisms by which this may occur are discussed.

Adrenal Glands↗
PubMed1994

Suppression of multi-drug resistance gene expression in the mouse liver by 1,4-bis[2,(3,5-dichloropyridyloxy)]benzene.

P-glycoproteins encoded by the (multi-drug resistance) mdr genes play a central role in the resistance of tumor cells to a wide range of anti-cancer drugs. Modulation of P-glycoprotein function could therefore provide a means of sensitising tumor cells to chemotherapy. Studies in this context have centred around the use of compounds which antagonise the P-glycoprotein membrane transport system. To investigate the possibility of modulating P-glycoprotein expression at a transcriptional level, we investigated the effects of hormonal factors and cytochrome P450-inducing agents on hepatic expression of murine mdr 1, mdr 2 and mdr 3. Hepatic mdr 2 and mdr 3 expressions were significantly suppressed in hypophysectomised animals, indicating that pituitary hormones activate the hepatic expression of these genes. Many of the foreign compounds and anti-cancer drugs tested did not significantly induce mdr 1, 2 or 3 expression. However, it was of particular interest that a potent cytochrome P450 inducer, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, almost completely suppressed hepatic mdr 2 and 3 expressions.

Animals↗
PubMed1994

Deduced amino acid sequence of a murine cytochrome P-450 Cyp4a protein: developmental and hormonal regulation in liver and kidney.

Proteins from the cytochrome P-450 CYP4A gene family metabolise hormones such as prostaglandins and other fatty acids, and are induced by peroxisome proliferators such as the hypolipidaemic drugs clofibrate and ciprofibrate. In order to better understand the function and regulation of these enzymes we have cloned a murine cDNA, Cyp4a-10, whose deduced amino acid sequence shares 92% sequence identity with rat CYP4A1. The developmental and hormonal regulation of this protein and other members of the murine Cyp4a gene family were then studied using a polyclonal antibody to rat CYP4A1. The expression of Cyp4a proteins in liver and kidney develop gradually from birth and are sexually differentiated in mature animals; growth hormone appears to be involved in regulating expression of hepatic Cyp4a proteins. The administration of phenobarbital and dexamethasone affected the expression of Cyp4a proteins in the liver, but not in the kidney, where testosterone was the key regulatory factor, demonstrating interesting tissue-specific effects in the regulation of these enzymes.

Amino Acid Sequence↗
PubMed1994

Metabolism of [3-14C] coumarin by human liver microsomes.

1. The metabolism of 50 microM [3-14C] coumarin has been studied in a panel of 12 human liver microsomal samples of known P450 isoenzyme profile. 2. [3-14C] coumarin was metabolized by human liver microsomes to various polar products including 3-, 4- and 7-hydroxycoumarins (3-HC, 4-HC and 7-HC) 6,7-dihydroxycoumarin (6,7-DiHC), o-coumaric acid (o-CA), o-hydroxyphenyl-acetaldehyde (o-HPA), o-hydroxyphenylethanol (o-HPE), o-hydroxyphenylacetic acid (o-HPAA) and o-hydroxyphenylpropionic acid (o-HPPA) and to product(s) that bind covalently to microsomal proteins. 3. For all 12 subjects, mean rates of [3-14C] coumarin metabolism to total polar products (metabolism to all products except product(s) covalently bound to microsomal proteins), 7-HC, the 3-hydroxylation pathway (sum of 3-HC, o-HPA, o-HPE and o-HPAA), o-HPPA, 6,7-DiHC and covalent binding were 1420, 1230, 73.8, 52.5, 9.5 and 4.8 pmol/min/mg protein respectively. 4. Marked interindividual differences in [3-14C] coumarin metabolism to total polar products (30-fold variation) and 7-HC (2250-fold variation) were observed. 5. Good correlations were observed between [3-14C] coumarin metabolism and total polar products, 7-HC, o-HPPA and 6,7-DiHC, but not to 3-hydroxylation pathway products and levels of 2A6 and 2B6 in human liver microsomes. 6. [3-14C] coumarin metabolism to any polar products did not correlate with levels of 1A2, 2C8, 2C9, 2E1, 3A3/4 and 4A1 in human liver microsomes.

Biotransformation↗
PubMed1993

Alterations in rat hepatic drug metabolism during pregnancy and lactation.

The hepatic microsomal drug metabolism during pregnancy and lactation was studied. Four days post partum, the concentrations of cytochrome P450 and cytochrome b5 were reduced by 50% when compared with pregnant rats, at day 10 of gestation. Within this time period the N-demethylation of aminopyrine, the rate of aldrin epoxidation and the N-demethylation of demethylnitrosamine was reduced by 53, 74 and 21%, respectively. However, the rates of ethoxyresorufin-O-deethylation did not differ amongst both groups and the deethylation of 4-nitroanisole and the 4-hydroxylation of aniline was increased by 71 and 31%, respectively in lactating rats. Furthermore, the activities of UDP-glucuronyltransferase and glutathione S-transferase were increased by 21 and 27%, but those of epoxide hydrolase were reduced by 85%. Western immunoblot analysis of microsomal proteins obtained from pregnant and lactating rats shows that only proteins encoded by the genes of CYP2C6 and CYP3A1 are expressed at detectable levels, whereas the expression of CYP1A1, CYP1A2, CYP2A1, CYP2B1, CYP2E1 and CYP4A1 was not detectable in pregnant and lactating rats at a protein loading of 3 micrograms total protein per well. In contrast, in northern blot hybridization experiments, detectable amounts of mRNA of the above named isoenzymes were measurable, but at varying intensities. Based on the northern blot hybridization analysis, an approximate 4-fold and 3-fold increase in CYP2A1 mRNA and CYP3A1 mRNA was found, when lactating rats were compared with female controls or pregnant rats, at day 10 of gestation.

Animals↗