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Biomedical subjects

A O El-Kadi

Publications and source records attributed to A O El-Kadi.

10 recordsLinked to original sources
PubMed2003

The effect of a strongly basic alkaloidal fraction of Rhazya stricta, a traditional medicinal plant, on cytochrome P450-mediated metabolism of theophylline in mice.

The strongly basic alkaloidal fraction of the traditional medicinal plant Rhazya stricta (RS) was given orally to mice, in a single dose of 10 mg/kg (group 1) or, twice daily for 3 days at the same dose (group 2). A third group (control) received normal saline. Liver homogenates from all animals were used to assess the microsomal activity of cytochrome P450 and its isoforms as well as its catalytic activity (using theophylline as a substrate). RS alkaloidal fraction had no significant effect on the total amount of microsomal cytochrome P450, but it caused a significant increase in the cytochrome P450 isoforms CYPs 1A1 and 1A2. It also significantly increased the concentrations of some metabolites of theophylline. These results suggest that RS has the potential to interact with other drugs that are biotransformed by cytochrome P450, when given concomitantly with it.

Administration, Oral↗
PubMed2001

L-NAME prevents in vivo the inactivation but not the down-regulation of hepatic cytochrome P450 caused by an acute inflammatory reaction.

A turpentine-induced inflammatory reaction (TIIR) down-regulates multiple isoforms of hepatic cytochrome P450 (P450) and increases microsomal lipid peroxidation. Since the synthesis of nitric oxide (NO*) is stimulated by inflammatory reactions, and NO* can depress the P450, it was of interest to investigate in vivo whether L-NAME and theophylline, by its anti-inflammatory properties, could prevent the depression of P450 caused by a TIIR. Control and rabbits with a TIIR received L-NAME for 72 h, and the activity of P450 was assessed in vivo and in vitro. In vivo, TIIR reduced theophylline systemic clearance by 50% (p<0.05), P450 total content by 67%, and the amount of CYP1A1/2 proteins by around 60% (p<0.05). L-NAME partially prevented the decrease in theophylline systemic clearance and in P450 total content, as well as the increase in lipid peroxidation; however, L-NAME did not hinder CYP1A1/2 proteins down-regulation. L-NAME did not modify the in vitro ability of the serum of rabbits with TIIR to decrease P450 activity, suggesting that the effect of L-NAME is not associated to a decrease in serum mediators. As assessed by the concentration in seromucoids, theophylline did not modify the severity of the inflammatory reaction, nor did it prevent the decrease in P450 activity. In conclusion, a TIIR down-regulates and reduces P450 activity, decrease that is at least in part mediated by NO*; theophylline does not prevent TIIR-induced P450 decrease in activity.

Animals↗
PubMed2001

Cytochrome P450 down-regulation by serum from humans with a viral infection and from rabbits with an inflammatory reaction.

Serum from humans with an upper respiratory viral infection (HS(URVI)) and from rabbits with a turpentine-induced acute inflammatory reaction (RS(TIAR)) reduces the activity of hepatic cytochrome P450 (P450) following 4 h of incubation. The aim of the present study was to assess the effect of HS(URVI) and RS(TIAR) on P450 activity and expression following 24 h of incubation with hepatocytes from control (H(CONT)) and rabbits with a TIAR (H(INFLA)). RS(TIAR) incubated with H(CONT) for 24 h reduced P450 content and activity, and CYP3A6 by 45%, without changing CYP1A1 and 1A2; when incubated with H(INFLA), RS(TIAR) decreased P450 content and activity without affecting CYP1A1 or 1A2. HS(URVI) incubated for 4 h with H(CONT) decreased P450 activity without affecting the amounts of CYP1A1, 1A2, or 3A6, although when incubated for 24 h, P450 activity and CYP3A6 amount decreased. HS(URVI) incubated with H(INFLA) for 4 h reduced P450 content and activity, and incubated for 24 h reduced activity, P450 content, and amount of CYP1A1 and 1A2 proteins. The present study demonstrates that 1) the effect of RS(TIAR) and HS(URVI) depends upon the susceptibility of the hepatocyte, i.e., H(CONT) or primed H(INFLA); 2) P450 down-regulation is preceded by a decrease in P450 activity; 3) the nature of the inflammatory reaction determines the repercussions on P450 activity and expression; and 4) CYP3A6 is more vulnerable than CYP1A1 and 1A2 to the down-regulation provoked by an inflammatory challenge.

Animals↗
PubMed2000

Role of reactive oxygen intermediates in the decrease of hepatic cytochrome P450 activity by serum of humans and rabbits with an acute inflammatory reaction.

Serum of rabbits with a turpentine-induced acute inflammatory reaction (RS(INFLA)) and serum of humans with a viral infection (HS(INF)) were previously shown to diminish hepatic cytochrome P450 (P450) content and activity. To document the role of reactive oxygen intermediates in the serum-mediated decrease in P450 content and activity, hepatocytes of rabbits with an acute inflammatory reaction (H(INFLA)) were incubated with RS(INFLA) and HS(INF) for 4 h, and total P450 content (spectrally measurable P450), P450 activity (assessed by estimating the formation of theophylline metabolites), and amount of CYP1A1, CYP1A2, and CYP3A6 proteins were measured. RS(INFLA) or HS(INF) decreased P450 content and activity without affecting the amount of CYP1A1 and -1A2 H(INFLA). Exposure of H(CONT) or H(INFLA) to hydrogen peroxide (0.01-1.0 mM) and sodium nitroprusside (0.01-1.0 mM) produced a dose-dependent decrease in P450 content and in the formation of theophylline metabolites without modifying the amount of CYP1A1 and CYP1A2, whereas lipid peroxidation increased. Incubation of L-NAME (0.05-1.0 mM), dimethylthiourea (6.25-50 mM), or N-acetylcysteine (0.01-1.0 mM) with H(INFLA) partially prevented the decrease in P450 content and activity and the increased lipid peroxidation induced by RS(INFLA) and HS(INF). On the other hand, 3-amino-1,2,4-triazole (10-100 mM) or diethyldithiocarbamate (1.0-10 mM) potentiated RS(INFLA)- and HS(INF)-mediated decreases in P450 content and activity and the increase in lipid peroxidation, without affecting the amount of CYP1A1 or -1A2; DL-buthionine-(S,R)-sulfoximine (2.5-25 mM) potentiated only the inhibition of 1,3-dimethyluric acid formation. It is concluded that reactive oxygen intermediates are implicated in the decrease of H(INFLA) P450 content and activity induced by 4 h of exposure to RS(INFLA) or HS(INF).

Acute-Phase Reaction↗
PubMed1999

Effect of hypoxia alone or combined with inflammation and 3-methylcholanthrene on hepatic cytochrome P450 in conscious rabbits.

1 To investigate the effect of moderate hypoxia alone or combined with an inflammatory reaction or after 3-methylcholanthrene (3MC) pre-treatment on cytochrome P450 (P450), conscious rabbits were exposed for 24 h to a fractional concentration of inspired O2 of 10% (mean PaO2 of 34 mmHg). Hypoxia decreased theophylline metabolic clearance (ClM) from 1.73+/-0.43 to 1.48+/-0.13 ml min-1 kg-1 (P<0. 05), and reduced (P<0.05) the formation clearance of theophylline metabolites, 3-methylxanthine (3MX), 1-methyluric acid (1MU) and 1,3-dimethyluric acid (1,3DMU). Hypoxia reduced the amount of CYP1A1 and 1A2 but increased CYP3A6 proteins. 2 Turpentine-induced inflammatory reaction reduced (P<0.05) the formation clearance of 3MX, 1MU, and 1,3DMU, and diminished the amount of CYP1A1, 1A2 and 3A6 proteins. However, when combined with hypoxia, inflammation partially prevented the decrease in ClM, especially by impeding the reduction of 1,3DMU. The amount of CYP1A1 and 1A2 remained reduced but the amount of CYP3A6 protein returned to normal values. 3 Pre-treatment with 3MC augmented the ClM by 114% (P<0.05) due to the increase in the formation clearance of 3MX, 1MU and 1,3DMU. 3MC treatment increased the amount of CYP1A1 and 1A2 proteins. Pre-treatment with 3MC prevented the hypoxia-induced decrease in amount and activity of the P450. 4 It is concluded that acute moderate hypoxia and an inflammatory reaction individually reduce the amount and activity of selected apoproteins of the P450. However, the combination of hypoxia and the inflammatory reaction restores P450 activity to near normal values. On the other hand, pre-treatment with 3MC prevents the hypoxia-induced depression of the P450.

Animals↗
PubMed1998

Depression of the hepatic cytochrome P450 by an acute inflammatory reaction: characterization of the nature of mediators in human and rabbit serum, and in the liver.

There is increasing evidence suggesting that several mediators are involved in the cascade of events leading to the depression of the cytochrome P450 (P450) by an inflammatory reaction. The present study aimed to confirm the presence of mediators in the serum (RS(INFLA)) and hepatocytes (H(INFLA)) of rabbits with an acute inflammatory reaction, and in the serum of humans with an acute upper respiratory tract viral infection (HS(URTVI)). The inflammatory reaction was induced by the s.c. injection of 5 ml of turpentine. Incubation of RS(INFLA) or HS(URTVI) with H(INFLA) depressed the P450, diminished the formation of theophylline metabolites (3-methylxanthine, 1-methyluric acid, and 1,3-dimethyluric acid), and increased lipid peroxidation. The addition of preheated RS(INFLA) or HS(URTVI) to H(INFLA) did not diminish the amount of P450 or theophylline metabolites, and prevented the increase in lipid peroxidation. Incubating the filtrate of RS(INFLA) or HS(URTVI) dialyzed through membranes with cut-off of 10, 30, 50 and 100 kd, with H(INFLA) showed that rabbit and human mediators have molecular weights ranging from 10 to 30 kd. Incubation of H(INFLA) with hepatocytes from control rabbits (H(CONT)) did not decrease further the P450. However, when RS(INFLA) was added to co-cultured H(CONT) + H(INFLA), the depression of P450 was 37% greater (p<0.05), and the amount of theophylline metabolites generated was around 30% (p<0.05) smaller than that observed when H(CONT) or H(INFLA) were incubated with RS(INFLA). Based on the present results we may speculate that human and rabbit serum mediators are proteins of molecular weights ranging from 10 to 30 kd, and in addition, primed hepatocytes once exposed to the serum mediators release mediators able to depress the P450 in H(CONT).

Acute-Phase Reaction↗
PubMed1997

The influence of chronic treatment with clonidine, yohimbine and idazoxan on morphine withdrawal.

Numerous previous attempts have been made to study the involvement of alpha2-adrenoceptors in the expression of morphine withdrawal by studying the effects of selective alpha2-agonists and antagonists administered immediately before precipitation of withdrawal by an opioid antagonist such as naloxone. In the present investigation, we examined the effects of chronic treatment with clonidine (alpha2-agonist), idazoxan and yohimbine (alpha2-antagonists), concomitantly administered with morphine, on the expression of the withdrawal signs. In contrast to their acute effects, clonidine potentiated, while yohimbine and idazoxan attenuated the withdrawal signs precipitated by naloxone in morphine-dependent mice. In addition, mice chronically treated only with yohimbine displayed withdrawal signs similar to those reported with morphine withdrawal and these signs were not influenced by naloxone administration. Mice chronically treated with clonidine displayed withdrawal signs similar to those reported with morphine withdrawal and these signs were further potentiated by naloxone administration. The results suggest that down-regulation of alpha2-adrenoceptors by morphine is a major adaptation contributing to development of dependence on opioids and also point the way to more effective treatment of narcotic dependence. This suggestion was based on the hypothesis that the suppression of noradrenergic system during chronic morphine treatment by alpha2-antagonists might diminish noradrenergic hyperactivity and consequently the development of dependence and withdrawal signs.

Adrenergic Agents↗
PubMed1997

Down-regulation of the hepatic cytochrome P450 by an acute inflammatory reaction: implication of mediators in human and animal serum and in the liver.

1. Infection and inflammation trigger a cascade of mediators that eventually will down-regulate the hepatic cytochrome P450 (P450). The present study aimed to characterize the mediators contained in the serum of rabbits with an acute inflammatory reaction (AIR) induced by the s.c. injection of turpentine (5 ml), and in the serum of humans with an acute upper respiratory tract viral infection. 2. Hepatocytes from control (H(CONT)) rabbits and rabbits with an AIR (H(INFLA)) were isolated and cultured. Compared with H(CONT) in H(INFLA) the production of theophylline metabolites, 3-methylxanthine (3MX), 1-methyluric acid (1MU), and 1,3-dimethyluric acid (1,3DMU) was reduced as was the amount of total P450, while lipid peroxidation was increased. Incubation of H(INFLA) with serum of rabbits with an AIR (RS(INFLA)) for 4 h further reduced the formation of the metabolites of theophylline as well as the amount of P450, and enhanced the lipid peroxidation. RS(INFLA) obtained 6, 12 and 24 h after the injection of turpentine showed the same ability to down-regulate hepatic P450 as the serum obtained at 48 h. 3. The efficacy (Emax) of RS(INFLA) to inhibit the formation of theophylline metabolites differed, i.e. 1,3DMU > 1MU > 3MX, and the potency of serum mediators (IC50) was similar for 3MX and 1MU, but lower for 1,3DMU. 4. Incubation of serum of human volunteers (HS(INFLA)) with a viral infection with H(CONT) or H(INFLA) reduced the production of theophylline metabolites, as well as the amount of P450, and increased the lipid peroxidation. HS(INFLA) depressed 1,3DMU more efficiently than 3MX and 1MU. HS(INFLA) reduced 3MX with greater efficacy than did RS(INFLA). Potency was very variable but not different from rabbits. 5. It is concluded that the serum of rabbits with an AIR or of humans with a viral infection contain several mediators that inhibit noncompetitively various isoenzymes of the hepatic P450. The decrease in P450 induced by HS(INFLA) or RS(INFLA) is closely associated with the increase in lipid peroxidation (r2= 0.8870) suggesting that lipid peroxidation could directly or indirectly be involved in the P450 down-regulation.

Animals↗
PubMed1997

In vivo, ex vivo, and in vitro effects of L-NAME and L-arginine on the metabolism of theophylline in the rabbit.

It has been shown that selected isoforms of cytochrome P450 (P450) can generate nitric oxide from L-arginine analogs; however, the effect of L-arginine analogs on the catalytic activity of P450 remains unknown. To assess the effect of N-nitro-L-arginine methyl ester (L-NAME; 25 mg/kg) and L-arginine (150 mg/kg) on the activity of P450, these compounds were administered intravenously every 8 hr for 2 days to groups of six New Zealand rabbits. Thereafter, the biotransformation of theophylline was documented in vivo (2.5 mg/kg i.v.) and ex vivo in hepatocytes of control and treated animals. In vivo, compared with control rabbits, both L-NAME and L-arginine increased theophylline plasma concentrations secondary to a reduction in theophylline systemic clearance by 46% and 42% (p < 0.05), respectively. Ex vivo, the effect of L-arginine analogs on P450 activity was documented by measuring the production of 3-methylxanthine (3MX), 1-methyluric acid (1MU), and 1,3-dimethyluric acid (1,3DMU) after incubation of theophylline (176 microM) with hepatocytes for 4 hr. L-NAME reduced the formation of 3MX, 1MU, and 1,3DMU by 42%, 45%, and 32% (p < 0.05), respectively. However, L-arginine reduced only the formation of 3MX by 34% (p < 0.05). In the in vitro studies, incubation of L-NAME or L-arginine with hepatocytes did not modify the biotransformation of theophylline. It is concluded that L-NAME and L-arginine inhibit the activity of several apoenzymes of P450, the probable mechanism being a catalysis-dependent inhibition.

Animals↗