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Biomedical subjects

A Kazusaka

Publications and source records attributed to A Kazusaka.

At least 37 records · Page 2Linked to original sources
PubMed1999

Decrease in hepatic CYP2C11 mRNA and increase in heme oxygenase activity after intracerebroventricular injection of bacterial endotoxin.

We previously reported (Arch. Toxcol. 1998, 72, 492-498) that the differential decrease in the levels of hepatic cytochrome P450 (CYP) isozymes in rats was observed 24 hr after intracerebroventricular (i.c.v.) injection of bacterial lipopolysaccharide (LPS) at the dose ineffective (0.1 microgram) when injected intraperitoneally (i.p.). Among CYP isozymes we examined, the male specific CYP isozyme, CYP2C11 was most severely affected by i.c.v. injection of LPS. In this study, we examined the gene expression of CYP2C11, the total P450 contents, the CYP2C11-dependent activity of imipramine N-demethylase (IMND) and protein of CYP2C11 10 hr after i.c.v. or i.p. injections of LPS. Intracerebroventricular injection of LPS significantly decreased the level of CYP2C11 mRNA (to 63% of saline i.c.v. control), the total P450 contents (to 70% of saline i.c.v. control), the IMND activity (to 74% of saline i.c.v. control), but not protein of CYP2C11 in rat liver. In contrast, i.p. injection of LPS at the same dose as i.c.v. did not significantly affect these parameters. Since CYP is a heme protein, we also measured the activity of heme oxygenase (HO) using the same rat liver microsomes. The HO activity was increased to 166% by i.c.v. injection of LPS and 135% by i.p. injection of LPS compared to corresponding saline control. It is suggested that i.c.v. injection of LPS down-regulates the expression of CYP2C11 at transcriptional level and that both the decrease in CYP2C11 mRNA and the increase in heme degradation may be involved in the decreased level of protein and activity of CYP2C11 by i.c.v. injection of LPS in rat liver.

Adrenergic Uptake Inhibitors↗
PubMed1999

Effects of concurrent exposure to 3-methylcholanthrene and vitamin A on fetal development in rats.

To investigate the effect of the environmental pollutants, polycyclic aromatic hydrocarbons (PAHs), on retinoic acid-induced teratogenesis, all-trans-retinoic acid (RA) dissolved in corn oil (120 mg/kg) was administered orally to pregnant rats at the 11th day of gestation with and without the prior intraperitoneal treatment with 10 mg/kg 3-methylcholanthrene (3-MC) for 3 days. Dams were killed on the 20th day of pregnancy. The examinations of fetuses revealed that 3-MC barely enough to cause induction of P-450 in pregnant dams had profound embryo-toxic effects: the fetal resorption amounted to approximately 60% of total number of implantations. The fetuses survived weighed less than the control fetuses. All of RA-treated mothers had fetuses with abnormalities, and the main malformations were absence of tail (100%), caudal and sacral malformations (100%), and cleft palate (42%). Pregnant dams received both 3-MC and RA had a reduced severity of tail anomaly (33%), while the rest, 67%, had short vestigial tail. Caudal and sacral malformations were detected but at a milder degree. We did not observe cleft palate in this group. The concurrent treatment of dams with 3-MC and RA led to an increased inducibility of cytochrome P-450 and subsequently, CYP1A1 dependent enzyme activity higher than those observed after the injection of 3-MC alone. UDP-glucuronyl-transferase activity was also markedly induced in concurrent 3-MC and RA group higher than that in 3-MC alone. We suggest that the induction of P-450 and alteration of metabolic enzyme activities may play an important role in reducing the teratogenic potency of RA. However, RA-treatment did not retard the embryo-toxic effect of 3-MC but rather potentiated.

Abnormalities, Drug-Induced↗
PubMed1998

Strain differences in CYP3A-mediated C-8 hydroxylation (1,3,7-trimethyluric acid formation) of caffeine in Wistar and Dark Agouti rats. Rapid metabolism of caffeine in debrisoquine poor metabolizer model rats.

We observed significant strain differences [Dark Agouti (DA) > Wistar] in 1,3,7-trimethyluric acid formation (C-8 hydroxylation) during caffeine metabolism, though not in N-demethylations, in adult male DA and Wistar rats. In contrast, adult female and immature male rats of both DA and Wistar strains did not show significant differences in activity levels of C-8 hydroxylation. Kinetic studies using liver microsomes revealed that adult male DA rats have a larger Vmax for C-8 hydroxylation than do Wistar rats. Troleandomycin (TAO), known as a cytochrome P450 (CYP) 3A inhibitor, and an anti-rat CYP3A2 polyclonal antibody effectively reduced C-8 hydroxylation by rat liver microsomes in a concentration-dependent manner, suggesting that C-8 hydroxylation in rats is mediated largely by an isoform(s) of the CYP3A subfamily. Troleandomycin and the antibody did not inhibit the N-demethylations of caffeine by rat liver microsomes. Treatment of rats with CYP3A inducers caused a marked increase in C-8 hydroxylase activity. These results indicate that the rat CYP3A subfamily is capable of catalyzing C-8 hydroxylation of caffeine as is the case for human CYP3A4. The results of western blotting analysis using anti CYP3A antiserum showed that the staining intensity of the protein band in DA rat liver microsomes was higher than that in Wistar rat liver microsomes. We concluded that marked sex-dependent strain differences in C-8 hydroxylation of caffeine between Wistar and DA rats are due to the differences in the levels of expression of CYP3A in these strains of rats.

Aging↗
PubMed1998

Effects of the agrochemicals butachlor, pretilachlor and isoprothiolane on rat liver xenobiotic-metabolizing enzymes.

1. The herbicides butachlor (2-chloro-2',6',diethyl-N-[buthoxymethyl] acetanilide) and pretilachlor (2-chloro-2',6'-diethyl-N-[2-propoxyethyl] acetanilide) are widely used in Asia, South America, Europe and Africa. Isoprothiolane (diisopropyl-1,3-dithiolan-2-ylidenemalonate) is used as a fungicide and an insecticide in rice paddies. We administered these agrochemicals to the male rat and examined their effects on cytochrome P450 (P450), glutathione S-transferase (GST), UDP-glucuronosyltransferase (UDPGT), and NAD(P)H-quinone oxidoreductase 1 (NQO1)-related metabolism in the liver. 2. Administration of isoprothiolane, butachlor or pretilachlor to rat induced hepatic P4502B subfamily-dependent enzyme activities (pentoxyresorufin O-depentylation and testosterone 16 beta-hydroxylation) up to 271-413% of control, which coincided with the increase in expression levels of the P4502B apoprotein. 3. Activities of GST toward 1-chloro-2,4-nitrobenzene and 3,4-dichloronitrobenzene were slightly induced (127-133% of control) in the liver of the rat treated with these pesticides. On the other hand, marked elevations of UDPGT activities toward p-nitrophenol (164-281% of control) were observed. NQO1-related metabolism (menadione reductase activity) was also induced (123-176% of control) in the liver of rat treated with these agrochemicals. 4. These results indicate that some of the agrochemicals currently in use are capable of inducing phase I and II xenobiotic-metabolizing enzyme activities in an isozyme selective manner. The induction of these activities may disrupt normal physiologic functions related to these enzymes in exposed animals.

Acetanilides↗
PubMed1998

Expression and characterization of dog CYP2D15 using baculovirus expression system.

Dog CYP2D15 was expressed in Sf9 cells with a recombinant baculovirus. Infection of Sf9 insect cells with a recombinant dog CYP2D15-virus resulted in the expression of a protein which cross-reacted with a polyclonal antibody against a dog CYP2D15-specific peptide. The difference spectrum of CO-complex of reduced P450 of the infected cell microsomes had a maximal absorbance at 449 nm. The specific content of P450 was calculated to be 0.56 nmol/mg of Sf9 cell microsomal protein. Although the expressed dog CYP2D15 showed high catalytic activity for the hydroxylations of bunitrolol and imipramine at low substrate concentration (10 microM), the catalytic activity for that of debrisoquine (50 microM) was extremely low as compared with that of CYP2D from other species. Dog liver microsomes also showed bunitrolol and imipramine hydroxylase activities, but not debrisoquine hydroxylase activity at the same substrate concentrations. In addition, the expressed CYP2D showed high catalytic activity for imipramine N-demethylation. Thus, our study reveals that the expressed dog CYP2D15 engages in high catalytic activity and has a unique substrate specificity from other CYP2D subfamilies. Western blot analysis suggested that the dog CYP2D15 contents were less than 4% of the total liver P450 content, assuming that 100% of expressed CYP2D15 incorporated heme.

Animals↗
PubMed1998

Regio- and stereoselectivity in propranolol metabolism by dog liver microsomes and the expressed dog CYP2D15.

We have studied the regio- and stereoselectivity of ring-hydroxylation and N-desisopropylation of S(-)- and R(+)-propranolol, using dog liver microsomes and the expressed dog CYP2D15 in insect cells. In dog liver microsomes, 4-hydroxylation was the preferred pathway in S(-)-propranolol oxidation, while N-desisopropylation was the preferred pathway in R(+)-propranolol oxidation. S(-)-Propranolol was preferred over R(+)-propranolol as substrate for 4- and 5-hydroxylations, while R(+)-propranolol was the preferred substrate for N-desisopropylation at higher substrate concentrations. The expressed CYP2D15 had high catalytic activities toward 4-, 5-hydroxylation, as well as N-desisopropylation of both enantiomers. At the substrate concentrations used, 4-hydroxylation was the preferred pathway for the metabolism of both enantiomers, and S(-)-propranolol was the preferred substrate over R(+)-propranolol for all three monooxygenations catalyzed by CYP2D15. Anti-CYP2D15 peptide antibody strongly inhibited 4- and 5-hydroxylation of both enantiomers in dog liver microsomes, while it did not inhibit their N-desisopropylation. These findings suggest that CYP2D15 is highly responsible for the stereoselective 4- and 5-hydroxylations of propranolol in dog liver microsomes.

Animals↗
PubMed1998

Molecular basis of the Dark Agouti rat drug oxidation polymorphism: importance of CYP2D1 and CYP2D2.

The Dark Agouti rat has been proposed as a model for the human debrisoquine 4-hydroxylase polymorphism. Earlier studies suggested that the poor metabolizer phenotype in the Dark Agouti rat is caused by the absence of the expression of CYP2D1 mRNA. Although CYP2D1 is the major enzyme catalyzing debrisoquine 4-hydroxylation, other reports have indicated the involvement of a CYP2D, purified from rat hepatic microsomes and presumed to be CYP2D2, which also exhibits this activity. The levels of CYP2D1 and CYP2D2 mRNAs were markedly lower in Dark Agouti as compared to Sprague Dawley rats. Using a baculovirus expression system, recombinant CYP2D1 and CYP2D2 from Spodoptera frugiperda insect cells were examined and were found to both forms catalize debrisoquine 4-hydroxylase activity. These results suggest that reduced debrisoquine 4-hydroxylase activity in the Dark Agouti rat is caused by the low level expression not only of CYP2D1, but also of CYP2D2. Interestingly, bunitrolol 4-hydroxylation was catalyzed by recombinant CYP2D2, while CYP2D1 was inactive toward this substrate. Thus, the low bunitrolol 4-hydroxylation in Dark Agouti rats was caused by the low level of CYP2D2 expression in this rat strain.

Adrenergic beta-Antagonists↗
PubMed1997

Activation of serum response factor in the liver of Long-Evans Cinnamon (LEC) rat.

We have studied the DNA binding activities of transcription factors in the liver of Long-Evans Cinnamon (LEC) rats, an animal model of Wilson's disease. Owing to a genetic defect, this strain of rats accumulates excessive copper in the liver and develops severe hepatitis and hepatocellular carcinoma. We found that the DNA binding activity of the serum response factor (SRF) was higher in the liver of LEC rats (approximately 2-fold) than in that of Wistar rats. There was a close correlation between the intensity of the activity and the concentrations of copper in the nuclear protein. The DNA binding activity of Sp1, on the other hand, showed similar levels in both LEC and Wistar rats. SRF may play an important role in the development of hepatocellular carcinoma in LEC rats by mediating the proto-oncogene c-fos induction. We suggest that the copper in nuclear protein may be involved in the activation of SRF.

Animals↗
PubMed1997

Isozyme selective alterations of the expression of cytochrome P450 during regeneration of male rat liver following partial hepatectomy.

1. During liver regeneration in the male rat, the metabolic activities of imipramine were differentially affected depending on the specific metabolic pathways. Imipramine N-demethylation was markedly reduced whereas 2-hydroxylation showed only a moderate reduction following partial hepatectomy. 2. A slight decline was observed in the hepatic microsomal content of CYP2D apoprotein, whereas a substantial decrease occurred in CYP2C11 content during liver regeneration. Since imipramine 2-hydroxylation and N-demethylation are mediated by CYP2D and 2C11 respectively, metabolic pathway-specific alterations in the activities of imipramine metabolism are explained by the isozyme selective alteration in the levels of CYPs in regenerating liver. 3. No significant effect of regeneration was observed on expression of CYP2B1 and 2E1 apoproteins. CYP3A2 apoprotein, one of the male-specific CYP isoforms, was significantly suppressed in regenerating liver showing a similar pattern of alteration to the levels of CYP2C11. The alteration pattern of the CYP1A1 level was different to the above with a moderate decline at the first day post-operation and a marked rebound thereafter. 4. In the partially hepatectomized male rate, no significant increase in androstenedione 5-alpha reductase activity, an activity predominant in the female rat, was detected. It is concluded that the pattern of alterations of hepatic oxidative metabolism during liver regeneration was not related to the functional feminization of the liver.

Androstenedione↗
PubMed1996

Mechanism for mouse strain differences in the protective effect of Sudan III against the in vivo genotoxicity of 7,12-dimethylbenz[a]anthracene.

The effect of Sudan III-pretreatment on the in vivo genotoxicity of 7,12-dimethylbenz[a]anthracene (DMBA) was investigated using C57BL/6 (B6) and DBA/2 (D2) mice. A significant increase in the frequency of micronucleated reticulocytes was observed in both strains of mice treated with DMBA. The increase was significantly reduced in B6 but not D2 mice by Sudan III-pretreatment. However, enhancement of metabolic activation was found in the Ames assay in the hepatic post-mitochondrial supernatant fraction (S9) from Sudan III-treated animals. It was greater with S9 from B6 than S9 from the D2 group. When the assay was performed in the presence of glutathione, this enhancement was significantly reduced. Sudan III induced some drug metabolizing enzymes, mainly CYP1A and glutathione S-transferase was also induced. The induction of CYP1A was more effective in B6 than D2 mice. These results support our hypothesis that the simultaneous induction of Phase I and II drug metabolizing enzymes is the mechanism for the chemoprevention by Sudan III and suggest that strong induction of CYP1A might be essential for a protective effect.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1996

Alterations of cytochrome P450-dependent monooxygenase activities in Eriocheir japonicus in response to water pollution.

Eriocheir japonicus, fresh-water crabs inhabiting rivers and estuaries in Japan, were investigated for cytochrome P450 (CYP)-dependent drug-metabolizing enzyme activities to see if these activities reflect the river pollution gradient. From the laboratory dose-response experiments, we found that the polycyclic aromatic hydrocarbon (PAH) 3-methylcholanthrene induced total CYP contents, ethoxycoumarin O-deethylase activity, and bunitrolol 4-hydroxylase activity in crab hepatopancreas. In the field studies, crabs collected from the river with the highest concentration of PAHs exhibited the highest levels of CYP, the highest activities of benzo[a]pyrene 3-hydroxylase, imipramine 2-hydroxylase, bunitrolol 4-hydroxylase, ethoxycoumarin O-deethylase, and the ability to metabolically activate benzo[a]pyrene, but erythromycin N-demethylase activity was not induced. The correlation between PAH levels and drug-metabolizing enzyme activities in female crabs were not as marked as in male crabs. The levels and activities of CYP did not appear to reflect the concentrations of organochlorines and polychlorinated biphenyl congeners (PCBs) studied in the fat of crab hepatopancreas.

Animals↗
PubMed1996

Effect of 3-methylcholanthrene on bunitrolol metabolism. Kinetics and immunological studies on 4-hydroxylation of bunitrolol catalyzed by two species of cytochromes P450 in rat liver microsomes.

Effect of the induction of cytochrome P4501A1 with 3-methylcholanthrene (3-MC) treatment on kinetics of bunitrolol (BTL) 4-hydroxylase activity of rat liver microsomes was investigated. The relationship between the rate and BTL concentration showed monophasic kinetics (KM = 0.74 +/- 0.13 microM) when microsomes from untreated rats were used, whereas microsomes from 3-MC-treated rats showed biphasic kinetics (KM1 = 0.76 +/- 0.13, KM2 = 646 +/- 16 microM). Anti-cytochrome P450 (P450) BTL (P4502D subfamily) antiserum inhibited the reaction > 90% when low concentrations (approximately 10 microM) of BTL were used in both microsomes. However, at high BTL concentrations (approximately 2,000 microM), the inhibition was only up to a half of control in microsomes from 3-MC-treated rats, whereas in microsomes from untreated rats, the rates were suppressed > 90%. Kinetics observed in microsomes from 3-MC-treated rats changed to nearly monophasic, with a KM value corresponding to KM2. Anti-P4501A1 IgG, on the other hand, hardly inhibited the reaction conducted by liver microsomes from 3-MC-treated rats when substrate concentrations were low, whereas at higher concentrations, it inhibited up to 50%, resulting in a monophasic kinetics with a KM value corresponding to KM1. These results clearly indicate that the biphasicity of kinetics in BTL metabolism in liver microsomes from 3-MC-treated rats is caused by the involvement of two P450 species: P450 BTL and P4501A1 in the reaction. This is the first direct evidence to the theoretical hypothesis that the biphasic kinetics of the enzyme reaction is caused by the involvement of at least two enzymes with different kinetic parameters.

Animals↗
PubMed1995

Purification and characterization of a form of cytochrome P450 from bear liver microsomes.

A form of P450 [termed P450(b-1)] was purified from male bear liver microsomes. The specific content of the final P450(b-1) preparation was 11.26 nmol/mg protein, and recovery was 0.20% of the microsomal P450. The apparent molecular weight of P450(b-1) was 54,000. The absorption spectrum of P450(b-1) indicated that this protein was a low- and high-spin mixed type P450 in the oxidized form. The carbon monoxide complex of reduced P450(b-1) showed an absorption peak at 450.5 nm. The reconstituted system containing P450(b-1) catalyzed the metabolism of aminopyrine, benzo[a]pyrene, 7-ethoxycoumarin, imipramine and propranolol, of which P450(b-1) most strongly catalyzed aminopyrine N-demethylation and imipramine N-demethylation. The N-terminal amino acid sequence of P450(b-1) was highly homologous to that of P450-D1 from liver microsomes of male beagle dogs. P450(b-1) showed similarities in spectral properties, N-terminal amino acid sequence, and catalytic activities to rat P450 2C11. P450(b-1) was immunochemically cross-reactive with anti-P450 2C11 antibody and very weakly cross-reactive with anti-P450 2E1 antibody, but did not react with anti P450 1A1 or 2B1 antibodies. On the basis of these results, we suggest that P450(b-1) belongs to the P450 2C subfamily.

Amino Acid Sequence↗
PubMed1995

Paradoxical effect of Sudan III on the in vivo and in vitro genotoxicity elicited by 7,12-dimethylbenz(a)anthracene.

Effect of the induction of drug metabolizing enzymes by Sudan III on the in vivo and in vitro genotoxicity elicited by 7,12-dimethyl-benz(a)anthracene (DMBA) was investigated. A significant suppression of DMBA-induced micronucleated reticulocytes was observed in C57BL/6 mice treated with Sudan III intraperitoneally for 3 or 5 days before injection of the DMBA. However, the preincubation of DMBA with hepatic microsomes from Sudan III-treated rats caused a marked increase in the in vitro mutagenicity in the Ames assay, paradoxically. Sudan III was found to induce CYP 1A1, 7-ethoxycoumarin O-deethylase activity as well as both UDP-glucuronyl transferase and glutathione S-transferase activities. The increase of mutagenicity of DMBA observed in the Ames assay using hepatic microsomes from Sudan III-treated rats was inhibited by the addition of uridine 5'-diphosphoglucuronic acid or reduced glutathione with cytosol. Mutagenic metabolites of DMBA formed by CYP1A1 appeared to be effectively detoxified by these phase II enzymes. The results of this study suggest that Sudan III-induced prevention of in vivo mutagenesis is due to the induction of both CYP 1A1 and detoxifying phase II enzymes. The induced CYP1A1 may accelerate formation of active metabolic intermediates, but phase II enzymes are also induced and detoxify these intermediates to inactive metabolites. This would reduce residence time of the carcinogen in the body and the time of exposure to active metabolites for target organs.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1995

Alterations in activation and deactivation of mutagens in aging rat liver.

Age-associated alternations in activation and deactivation of benzo[a]pyrene (BP), furylfuramide (AF2), and 2-nitrofluorene (NF) in rat liver were investigated. A modified Ames mutagenicity test system used liver 9000 g supernatant (S-9) from male Fischer 344 rats aged 3, 6, 12, and 24 months fortified with NADPH generating system alone or together with cofactors of conjugating enzymes. The numbers of revertant colonies due to mutagenic activation of BP during preincubation were markedly high in young rats and decreased with aging. They were decreased by the addition of UDP-glucuronic acid (15 mM) or glutathione (30 mM), the cofactors of UDP-glucuronyl transferase and glutathione S-transferase, respectively, in the preincubation mixture. The difference in the BP activation by liver S-9 from different age groups almost disappeared by the addition of reduced glutathione. A direct mutagen, AF2, was not metabolized during preincubation in the absence of cofactors of conjugating enzymes, but detoxified up to about 50% by the addition of glutathione to the preincubation mixture containing liver S-9 from rats of any age group. Another direct mutagen, NF, was partly detoxified during preincubation by liver S-9 from 3-month-old rats more than by that from 24-month-old rats. It is suggested that incidence of chemical carcinogenesis may increase along with aging due to the altered xenobiotics metabolism.

Aging↗
PubMed1995

Anti-peptide antibodies to the P4502D subfamily in rat, dog and man.

1. In order to obtain specific antibodies of the P4502D subfamily, we generated two anti-peptide antibodies against synthetic peptides, DPAQPPRD (peptide A) and DPTQPPRH (peptide B). The sequence of peptide A occurs in rat P4502D2, P4502D4 and human P4502D6, whereas the sequence of peptide B occurs in the dog P4502D subfamily. These sequences are closely related to an epitope of liver/kidney microsomal autoimmune hepatitis. 2. In immunoblotting studies, the anti-peptide antibody against peptide A recognized a 49-KDa protein in microsomes derived from human lymphoblasts expressing P4502D6 and rat liver. It showed no crossreactivity with microsomes from dog liver. In contrast, the anti-peptide antibody against peptide B recognized a 49-KDa protein only in microsomes of dog liver. These indicate that each anti-peptide antibody has the specificity for the respective sequences of the members of P4502D subfamily, with the species investigated herein. 3. In immunoinhibition studies, the anti-peptide antibodies against peptide B inhibited bunitrolol 4-hydroxylation and propranolol 4,5-hydroxylation, which are mediated by the dog P4502D subfamily. These data suggest that the anti-peptide antibodies against peptide B bind to the native and denatured forms of the P4502D subfamily. 4. The present study has demonstrated that the anti-peptide antibodies against this region are useful for studying the members of the P4502D subfamily.

Adrenergic beta-Antagonists↗
PubMed1995

Purification and characterization of a dog cytochrome P450 isozyme belonging to the CYP2D subfamily and development of its antipeptide antibody.

Species differences in the metabolism of bunitrolol (BTL) and propranolol (PL) in liver microsomes from rats and dogs were investigated. Hepatic microsomes from dogs lacked the ability to catalyze PL 7-hydroxylation, which is mediated by the CYP2D subfamily in rats. This suggested that dogs might lack the CYP2D subfamily; however, the antibody against cytochrome P450 (P450) BTL (CYP2D2) recognized a protein of approximately 49 kDa in hepatic microsomes from dogs, indicative of the presence of the CYP2D subfamily in dogs. The P450 purified from dog hepatic microsomes was designated P450 Canis familiaris (CF)1. It cross-reacted with the antibody against P450 BTL. The apparent molecular weight of the purified P450 CF1 was estimated to be 49 kDa. Its N-terminal amino acid sequence resembled the sequences of the members of the rat CYP2D subfamily and was the same as the sequences of the dog CYP2D subfamily, as deduced from the cDNA, except for the lack of four residues at the N-terminal. P450 CF1 could mediate metabolism of BTL and PL. P450 CF1, however, could not mediate PL 7-hydroxylation, which is almost exclusively mediated by CYP2D in rats. These findings indicate that P450 CF1 belongs to the CYP2D subfamily and that it differs functionally from the rat CYP2D subfamily. An antipeptide antibody against the synthetic peptide (DPTQPPRH), the sequence of which occurs in dog CYP2D at position 266-273 (S. Kirita et al., unpublished data), inhibited BTL 4-hydroxylase activity by 71% in dog hepatic microsomes at the substrate concentration of 0.01 M. This is further evidence that the CYP2D subfamily, in particular P450 CF1, is largely responsible for the oxidation of beta-blockers in dog hepatic microsomes.

Adrenergic beta-Antagonists↗