Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Infection of mice with Leishmania donovani resulted in decreased activities of several liver enzymes involved in the metabolism of xenobiotics. Microsomal membranes from infected livers contained reduced amounts of cytochromes P450 and b5 and NADPH-cytochrome P450 reductase. Several cytochrome P450 isoenzymes (P450-PB1, P450-PB3, P450-PCN and P450-UT1) and P450-mediated reactions (aminopyrine demethylase, aniline hydroxylase, benzphentamine demethylase and ethoxycoumarin deethylase) were affected similarly. The metabolism of two carcinogens (nitrosodimethylamine and 7,12-dimethylbenz[a]anthracene) by liver microsomal membrane preparations was also reduced. Leishmania infection caused an increase of cytosolic epoxide hydrolase and microsomal epoxide hydrolase and NADH-cytochrome b5 reductase were unaffected. The results suggest that Leishmania-infected animals are likely to have altered responses to exogenous toxins compared to uninfected animals.
Mol Biochem Parasitol 1990 Jun
PMID:Changes in hepatic xenobiotic-metabolising enzymes in mouse liver following infection with Leishmania donovani. 211 55

We present a strategy to elucidate the rate-limiting steps in activation of carcinogenic compounds by cytochromes P450. The principle was to select Reuber rat hepatoma cells for resistance to a procarcinogen. The hypothesis was that resistant cells should be systematically deficient in the P450 enzyme(s) involved in the activation process. Here we present an example of the use of this approach using aflatoxin B1 (AFB1), a potent hepatocarcinogen, as the selective agent. Parental cells as well as individual and pooled colonies selected for AFB1 resistance from three independent rat hepatoma lines were characterized for their content of 1) mRNA hybridizing to cDNA and/or oligonucleotide probes for cytochromes P450IIB1, P450IIB2 and albumin; and 2) aldrin epoxidase activity. Parental aflatoxin B1-sensitive cells were shown to express P450IIB1 but not P450IIB2. The majority of the aflatoxin B1-resistant clones failed to accumulate cytochrome P450IIB1 mRNA and expressed no or only very low aldrin epoxidase activity. Albumin mRNA levels remained unchanged, demonstrating that loss of expression of cytochrome P450IIB1 was not a consequence of a general dedifferentiation event. A revertant population showing restoration of both cytochrome P450IIB1 mRNA accumulation and aldrin epoxidase activity was fully sensitive to aflatoxin B1. The correlation between expression of cytochrome P450IIB1 and sensitivity to aflatoxin B1 in both parental cells and revertants strongly suggests that cytochrome P450IIB1 is a major contributor to the activation of aflatoxin B1 in rat hepatoma cells. The kind of strategy described here could be applied to other compounds that become cytotoxic for hepatoma cells following activation by cytochromes P450.
Mol Gen Genet 1990 Jul
PMID:Genetic analysis of aflatoxin B1 activation in rat hepatoma cells. 212 92

The histochemical activities of the enzymes alcohol dehydrogenase with propanol (A-D I) and isopropanol (A-D II) as substrates, 3- beta-hydroxysteroid dehydrogenase (3 beta .OHST-D), nicotinamideadenine dinucleotide phosphate (reduced form)-tetrazolium reductase (NADPH2-TR) and glucose-6-phosphate dehydrogenase (G6P-D) were studied in the testis of 6 cats daily injected with 20 micrograms/kg of the LHRH-analogue DTRP6-DGLY-10, LHRH-ethylamide (LHRH-A Group) and 3 cats injected with saline during 67 days. A morphometric analysis was done to evaluate the activity of the enzymes, its distribution and volume fractions of the Leydig cells with every activity. A-D II displayed a significant inhibition in the Leydig cells of the LHRH-A Group. There were no changes in the activities of G6P-D, 3 beta .OHST-D and NADPH2-TR, but it was possible to disclose some reduction of the volume fraction of the Leydig cells when the first two enzymes were used as its marker. This study corroborates that A-D II is a reaction in the pathway of steroidogenesis but does not explain whether it corresponds actually to 20-22 desmolase as proposed in the work by Hardonk (1965) or to another reaction linked to the activities of the cytochromes P450.
Cell Mol Biol 1990
PMID:Effect of a luteinizing-hormone-releasing-hormone (LHRH)-analogue on the histochemistry of the secondary alcohol-dehydrogenase in the Leydig cells of the cat testis. 222 54

Phenobarbital induces cytochromes P450 (P450s) of not only the class IIB gene subfamily (i.e., P450b and P450e) but also the class IIIA gene subfamily (P450p and P450pcn2). To determine whether coinduction of these structurally dissimilar gene products involves the same mechanism, we examined the dose dependency of phenobarbital induction of the mRNAs for these four P450s in a new responsive system for primary monolayer cultures of adult rat hepatocytes on Matrigel, a reconstituted basement membrane. Two-day treatments of the cultures with phenobarbital produced marked dose-dependent increases in the levels of P450b, P450e, and P450p mRNAs, which reached maximal inductions ranging from 11- to greater than 193-fold. Although the dose-response relationships for the inductions of P450b and P450e mRNAs by phenobarbital were similar (ED50 = 1.5 x 10(-5) and 5.7 x 10(-6) M, respectively), the dose-response curve for the induction of P450p mRNA was positioned distinctly to the right (ED50 = 3.0 x 10(-4) M). This difference reflects a potency ratio of 20-fold for P450p/P450b mRNA induction. Phenobarbital also produced a weak dose-dependent induction of P450pcn2 mRNA, with a potency (ED50 = 3.4 x 10(-5) M) intermediate between those for P450b/e and P450p. In a similar experiment using two phenobarbital-like inducers, (trans)nonachlor and clotrimazole, the relative inductions of P450b, P450e, P450p, and P450pcn2 mRNAs proved to be similar to those produced by phenobarbital (P450p/P450b potency ratios = 14- and 16-fold, respectively). These findings provide strong further evidence in support of the newly emerging concept that "phenobarbital" induction of the responsive class IIB and class IIIA P450 isozymes likely reflects multiple mechanisms.
Mol Pharmacol 1990 Oct
PMID:Differentiated induction of cytochrome P450b/e and P450p mRNAs by dose of phenobarbital in primary cultures of adult rat hepatocytes. 223 86

The gene coding for benzoate-para-hydroxylase (bphA) of Aspergillus niger was cloned using differential hybridisation techniques and complementation of mutants deficient in this enzyme activity. The nucleotide sequence of the gene was determined, the presence of two introns was shown and the transcription start and termination sites were determined. The structure of the mRNA upstream from the long open reading frame (ORF) is unusual. It contains two small, overlapping ORFs whose function is unknown. Comparison of the deduced amino acid sequence of the protein with the sequences present in the databanks, indicated a significant similarity of BPH to the superfamily of cytochrome P450 enzymes. Further analysis revealed that this protein is a member of a new P450 gene family designated P450LIII. The gene is designated CYP53. To increase the BPH activity of A. niger, multiple copies of the bphA gene were introduced into the genome of a recipient strain by transformation. Although increased intracellular levels of the BPH protein could be detected, the BPH enzyme activity was decreased, suggesting titration of another essential component.
Mol Gen Genet 1990 Sep
PMID:Isolation and molecular characterisation of the benzoate-para-hydroxylase gene (bphA) of Aspergillus niger: a member of a new gene family of the cytochrome P450 superfamily. 225 Jun 47

R76713 is a novel triazole derivative which selectively blocks the cytochrome P450-dependent aromatase. In human placental microsomes, in FSH-stimulated rat and human granulosa cells and in human adipose stromal cells, 50% inhibition of estradiol biosynthesis was obtained at drug concentrations of 2-10 nM. In PMSG-injected female rats, R76713 lowered plasma estradiol levels by 50 and 90% 2 h after single oral doses of 0.005 and 0.05 mg/kg respectively. After 1 mg/kg, estradiol levels were suppressed by 90% for 16 h. In male cynomolgus monkeys, R76713 dose-dependently (0.03-10 micrograms/kg) inhibited peripheral aromatization with an ED50 of 0.13 microgram/kg without altering metabolic clearance rates and conversion ratios. In vitro R76713 had no effect on other P450-dependent steroidogenic enzymes up to 1000 nM at least. In rats, LHRH-, ACTH- and sodium-deprived diet stimulated plasma testosterone, corticosterone and aldosterone levels were not modified 2 h after single oral administrations of R76713 (up to 20 mg/kg). Furthermore, R76713 did not show any in vitro or in vivo estrogenic or antiestrogenic property. R76713 also induced regression of DMBA-induced mammary tumors after daily oral administration of 1 mg/kg b.i.d. In male volunteers (n = 4), a single oral dose of 5 and 10 mg lowered median plasma estradiol levels from 70 pM to the detection limit of the assay (40 pM) 4, 8 and 24 h after intake whereas no changes were detected after placebo administration. In premenopausal women (n = 15), receiving a single oral dose of 20 mg, median plasma estradiol levels decreased from 389 pM (before) to 168, 133 and 147 pM, 4, 8 and 24 h after intake whereas they remained above 420 pM after placebo (n = 7).
J Steroid Biochem Mol Biol 1990 Nov 20
PMID:New non-steroidal aromatase inhibitors: focus on R76713. 225 38

Evidence accumulating in the literature supports the concept that insulin-like growth factor I (IGF-I) may be an important local regulator of ovarian function. Recent studies have demonstrated that IGF-I synergistically augments LH stimulation of theca-interstitial cell (TIC) androgen biosynthesis. The purpose of the present studies was to begin to elucidate the molecular mechanisms of the interaction between IGF-I and LH. TIC were purified from ovaries of hypophysectomized immature rats by Percoll gradient centrifugation. When isolated TIC (5 x 10(6) viable cells per dish) were cultured (4 days) in serum-free medium, low amounts (less than 10 ng/ml) of androsterone were produced. Basal androsterone production was not changed by incubation with IGF-I (30 ng/ml). Treatment with LH (50 ng/ml) caused an 85-fold stimulation of androsterone synthesis that was further increased 2.1-fold by concomitant treatment with IGF-I. Immunoblot analysis demonstrated that untreated TIC contained low levels of 17 alpha-hydroxylase/C17-20 lyase enzyme (P450(17 alpha] that were unchanged by incubation with IGF-I alone. LH treatment increased P450(17 alpha) content 5.5-fold and coincubation with LH plus IGF-I increased P450(17 alpha) content 16-fold above control levels. Cholesterol side chain cleavage enzyme (P450scc) was readily detected in immunoblots from untreated TIC. P450scc content was increased 2.6-fold by LH treatment and 4.2-fold by LH plus IGF-I. Interestingly, IGF-I alone induced a 2-fold increase in P450scc. To determine if the increases in P450scc content were associated with increased enzyme activity, progesterone production was measured.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Endocrinol 1990 Mar
PMID:Insulin-like growth factor-I selectively stimulates cholesterol side-chain cleavage expression in ovarian theca-interstitial cells. 234 81

Intestinal cytochromes P450 (P450) may function in the "first pass" metabolism of drugs, the detoxification of xenobiotics, or the activation of carcinogens. However, little is known about the expression of specific P450 genes in intestinal mucosa. We have previously shown that a P450 mRNA that is homologous to rat liver P450IIB1 (P450b) is expressed in rat small intestine and is inducible by phenobarbital, polyhalogenated biphenyls, and organochlorine pesticides. However, there are multiple highly homologous genes in the IIB subfamily and, therefore, studies using liver-derived cDNAs or oligonucleotides based on those cDNAs cannot definitively establish the identity of the intestinal mRNA(s). The polymerase chain reaction was used to enzymatically amplify cDNA synthesized from intestinal and hepatic RNA, and the amplified segments were identified by Southern blot analysis. These studies demonstrated that the amplified segment of the phenobarbital-inducible P450 mRNA in intestine was identical to this same segment of the hepatic P450b mRNA; furthermore, this analysis showed that P450e was not expressed in intestine. To definitively establish the identity of the intestinal mRNA, the full coding sequence of the P450b mRNA was cloned from intestinal and hepatic RNA and sequenced. The sequences of the intestinal and hepatic cDNA were identical and coded for P450b; the deduced protein sequence in the F344 rat differed in one amino acid from the reported sequence in Sprague-Dawley rats and, thus, represents a different allele of the same gene. An increment in intestinal P450b mRNA was detected as early as 1 hr following a single intraperitoneal injection of phenobarbital; this prompt rise in mRNA suggested that transcriptional activation may be the primary mechanism for induction. Nuclear run-on experiments were performed using nuclei isolated from intestinal mucosa 3 and 6 hr following treatment with phenobarbital. The rate of transcription of the P450IIB1 gene was increased approximately 6-fold 6 hr following phenobarbital; this was very similar to the increment in P450b mRNA as measured by quantitative dot blot analysis. Therefore, the predominant mechanism for the induction of P450b mRNA in intestine in response to phenobarbital was an increase in gene transcription. These studies indicate that the same member of the P450IIB subfamily, P450IIB1 or P450b, is expressed and inducible by similar mechanisms in small intestine and liver. Although putative P450b mRNA and apoprotein have been identified in lung and testes, the capacity for induction by phenobarbital, and presumably other xenobiotics, is unique to liver and intestine.(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Pharmacol 1990 Jun
PMID:P450IIB gene expression in rat small intestine: cloning of intestinal P450IIB1 mRNA using the polymerase chain reaction and transcriptional regulation of induction. 235 2

Total RNA from normal and anencephalic human fetal adrenals was examined by blot analysis for transcripts encoding P-450scc, P-450(11) beta, P-450(17) alpha, P-450C21 and adrenodoxin using bovine cDNA clones specific for these different enzymes. The specific contents of RNA encoding these components of the adrenocortical steroidogenic pathway were found to be similar in both types of adrenal tissue. Likewise, immunoblot analysis showed comparable concentrations of P-450scc, P450(17) alpha and adrenodoxin protein to be present in adrenal tissues from normal and anencephalic human fetuses. Immunoblot analysis of homogenates of fetal sheep adrenals of increasing gestational age (85-145 days) showed constant levels of P-450scc and P-450(11) beta, but increasing P-450(17) alpha content, especially near term. Both sheep fetuses prior to 136 days gestational age and human anencephalic fetuses are known to have extremely low circulating levels of immunoreactive ACTH as well as very low adrenal adenylate cyclase activity. Thus, it is concluded that factors other than pituitary ACTH which operate independent of adenylate cyclase activation are required for the initial expression (imprinting) of steroid hydroxylase genes.
Mol Cell Endocrinol 1987 Apr
PMID:Ontogeny of adrenal steroid hydroxylases: evidence for cAMP-independent gene expression. 243 59

Rat cytochrome P450 2c (P450 gene IIC11) is a constitutive, male-specific hepatic enzyme which is suppressed greater than 90% by treatment with 3,4,5,3',4',5'-hexachlorobiphenyl (HCB) [H. N. Yeowell et al. (1987) Mol. Pharmacol. 32, 340-347]. HCB also decreases serum testosterone levels in adult male rats (greater than 98% loss). The present study assesses whether the suppression of P450 2c by HCB is a direct result of its effects on serum testosterone levels. Further, the site along the hypothalamic-pituitary-testicular axis at which HCB acts to depress testosterone secretion was examined. Administration of the synthetic androgen methyltrienolone to HCB-treated rats failed to prevent the suppression of P450 2c mRNA and its associated microsomal steroid 16 alpha-hydroxylase activity under conditions where it effectively reversed the large decrease in P450 2c mRNA and steroid 16 alpha-hydroxylase activity produced by castration. Hepatic steroid 6 beta-hydroxylase activity, which is catalyzed primarily by P450 2a (P450 gene IIIA2), was also suppressed by HCB and was not protected by methyltrienolone. Administration of either human chorionic gonadotropin, an analog of pituitary-derived luteinizing hormone, or the hypothalamic luteinizing hormone releasing hormone elevated serum testosterone levels to a much smaller extent in HCB-treated rats than in control rats. These results indicate that the effects of HCB on serum testosterone levels reflect its effects on testicular function rather than the pituitary or hypothalamus. However, the present study demonstrates that the consequential reduction in serum testosterone levels in HCB-treated rats is not causally related to the reduction in hepatic P450 2c levels. Thus, HCB must also act on some other regulatory mechanism involved in the expression of this protein.
 ...
PMID:Suppression of male-specific cytochrome P450 2c and its mRNA by 3,4,5,3',4',5'-hexachlorobiphenyl in rat liver is not causally related to changes in serum testosterone. 249 61


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