Cytochrome P450 phenotypic ratios for predicting herb‐drug interactions in humans

Gurley, Bill J.; Gardner, Stephanie F.; Hubbard, Martha A.; Williams, David; Gentry, W. Brooks; Cui, Yanyan; Ang, C. Y. W.

doi:10.1067/mcp.2002.126913

Cited by 319 publications

(285 citation statements)

References 59 publications

(72 reference statements)

Supporting

Mentioning

252

Contrasting

Unclassified

Order By: Relevance

“…These results are consistent with a previous report that showed no changes in the pharmacokinetics of the CYP3A4 substrates, midazolam and alprazolam (Markowitz et al, 2003, Gurley et al, 2005, Gurley et al, 2002. Therefore, our results demonstrate a differential induction of PGP and CYP3A4 in response to garlic extract, suggesting that garlic extract can induce intestinal PGP independent of effecting CYP3A4.…”

Section: Discussionsupporting

confidence: 82%

“…Currently, there are three studies that have investigated the effects of garlic on CYP450 drug metabolizing enzymes in humans (Gurley et al, 2002, Markowitz et al, 2003, Gurley et al, 2005. Using debrisoquine, midazolam, caffeine, and chlozoxazone as test substrates, Gurley et al showed that garlic oil decreases CYP2E1 activity by 39% and 22% in young and elderly volunteers, respectively, yet exhibits no effect on CYP1A2, 2D6, and 3A4 function (Gurley et al, 2002, Gurley et al, 2005.…”

Section: Introductionmentioning

confidence: 99%

“…Using debrisoquine, midazolam, caffeine, and chlozoxazone as test substrates, Gurley et al showed that garlic oil decreases CYP2E1 activity by 39% and 22% in young and elderly volunteers, respectively, yet exhibits no effect on CYP1A2, 2D6, and 3A4 function (Gurley et al, 2002, Gurley et al, 2005. Similarly, Markowitz et al confirmed that garlic exhibits no effect on CYP2D6 and CYP3A4 function in drug interaction studies of Kwai garlic M a n u s c r i p t Page 4 of 23 supplements from Lichtwer Pharma and dextromethorphane or alprozolam (Markowitz et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Garlic extract induces intestinal P-glycoprotein, but exhibits no effect on intestinal and hepatic CYP3A4 in humans

Hajda

Rentsch

Gubler

et al. 2010

European Journal of Pharmaceutical Sciences

View full text Add to dashboard Cite

; Fattinger, K (2010). Garlic extract induces intestinal P-glycoprotein, but exhibits no effect on intestinal and hepatic CYP3A4 in humans. Garlic extract induces intestinal P-glycoprotein, but exhibits no effect on intestinal and hepatic CYP3A4 in humans AbstractGarlic extracts have been shown to decrease drug exposure for saquinavir, a P-glycoprotein and cytochrome P450 3A4 substrate. In order to explore the underlying mechanisms and to study the effects of garlic on pre-systemic drug elimination, healthy volunteers were administered garlic extract for 21 days. Prior to and at the end of this period, expression of duodenal P-glycoprotein and cytochrome P450 3A4 protein were assayed and normalized to villin, while hepatic cytochrome P450 3A4 function and simvastatin, pravastatin and saquinavir pharmacokinetics were also evaluated. Ingestion of garlic extract increased expression of duodenal P-glycoprotein to 131% (95% CI, 105-163%), without increasing the expression of cytochrome P450 3A4 which amounted to 87% (95% CI, 67-112%), relative to baseline in both cases. For the erythromycin breath test performed, the average result was 96% (95% CI, 83-112%). Ingestion of garlic extract had no effect on drug and metabolite AUCs following a single dose of simvastatin or pravastatin, although the average area under the plasma concentration curve (AUC) of saquinavir decreased to 85% (95% CI, 66-109%), and changes in intestinal P-glycoprotein expression negatively correlated with this change. In conclusion, garlic extract induces intestinal expression of P-glycoprotein independent of cytochrome P450 3A4 in human intestine and liver. Accepted ManuscriptTitle: Garlic extract induces intestinal P-glycoprotein, but exhibits no effect on intestinal and hepatic CYP3A4 in humans This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractGarlic extracts have been shown to decrease drug exposure for saquinavir, a P-glycoprotein and cytochrome P450 3A4 substrate. In order to explore the underlying mechanisms and to study the effects of garlic on pre-systemic drug elimination, healthy volunteers were administered garlic extract for 21 days. Prior to and at the end of this period, expression of duodenal P-glycoprotein and cytochrome P450 3A4 protein were assayed and normalized to villin, while hepatic cytochrome P450 3A4 function and simvastatin, pravastatin and saquinavir pharmacokinetics were also evaluated. Ingestion of garlic extract increased expression of duodenal P-glycoprotein to 131% (95%CI, 105-163%), without increasing the expression of cytochrome P450 3A4 which amounted to 87% (95%CI, 67-112%), relative to baseli...

show abstract

Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Garlic extract induces intestinal P-glycoprotein, but exhibits no effect on intestinal and hepatic CYP3A4 in humans

Hajda

Rentsch

Gubler

et al. 2010

European Journal of Pharmaceutical Sciences

View full text Add to dashboard Cite

show abstract

“…In addition, the CAR activators, phenobarbital and 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) demonstrate male-specific Cyp2a4 induction (Wei et al, 2002). Lastly, St. John's wort mediated induction of CYP3A4 is greater in human females than males (Gurley et al, 2002). Gender differences in P450 induction are important to discern because of potential gender-specific side effects following pharmaceutical or environmental chemical exposure (Meibohm et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Gender-specific induction of cytochrome P450s in nonylphenol-treated FVB/NJ mice

Hernández

Chapman

Kretschmer

et al. 2006

Toxicology and Applied Pharmacology

View full text Add to dashboard Cite

Nonylphenol (NP) is a breakdown product of nonylphenol ethoxylates, which are used in a variety of industrial, agricultural, household cleaning, and beauty products. NP is one of the most commonly found toxicants in the United States and Europe and is considered a toxicant of concern because of its long half-life. NP is an environmental estrogen that also activates the pregnane X-receptor (PXR) and in turn induces P450s. No study to date has examined the gender-specific effects of NP on hepatic P450 expression. We provided NP at 0, 50 or 75 mg/kg/day for 7 days to male and female FVB/NJ mice and compared their P450 expression profiles. Q-PCR was performed on hepatic cDNA using primers to several CYP isoforms regulated by PXR or its relative, the constitutive androstane receptor (CAR). In female mice, NP induced Cyp2b10 and Cyp2b13, and downregulated the female-specific P450s, Cyp3a41 and Cyp3a44. In contrast, male mice treated with NP showed increased expression of Cyp2a4, Cyp2b9, and Cyp2b10. Western blots confirmed induction of Cyp2b subfamily members in both males and females. Consistent with the Q-PCR data, Western blots showed dose-dependent downregulation of Cyp3a only in females and induction of Cyp2a only in males. The overall increase in female-predominant P450s in males (Cyp2a4, 2b9) and the decrease in female-predominant P450s in females (Cyp3a41, 3a44) suggest that NP is in part feminizing the P450 profile in males and masculinizing the P450 profile in females. Testosterone hydroxylation was also altered in a genderspecific manner, as testosterone 16α-hydroxylase activity was only induced in NP-treated males. In contrast, NP-treated females demonstrated a greater propensity for metabolizing zoxazolamine probably due to greater Cyp2b induction in females. In conclusion, NP causes gender-specific P450 induction and therefore exposure to NP may cause distinct pharmacological and toxicological effects in males compared to females.

show abstract

“…Many herbal and dietary products modulate cytochrome P450 activity. Gurley et al (2002) used single-time point phenotypic metabolic ratios to determine whether long-term supplementation of St John's wort, garlic oil, P. ginseng and Ginkgo biloba affected CYP1A2, CYP2D6, CYP2E1 and CYP3A4 activities in humans; no significant effect was observed for P. ginseng. In agreement with this, Gurley et al (2005) observed that the concomitant ingestion of P. ginseng with prescription medications in elderly patients resulted in only slight inhibition (7%) of CYP2D6 activity.…”

Section: Antigenotoxic Effects Of Panax Ginseng 949mentioning

confidence: 99%

Protection by Panax ginseng C.A. Meyer against the genotoxicity of doxorubicin in somatic cells of Drosophila melanogaster

et al. 2008

View full text Add to dashboard Cite

Panax ginseng is one of the most widely prescribed herbal medicines for the treatment of cancer, diabetes, chronic inflammation, and neurodegenerative and cardiovascular diseases. Since the use of alternative medicines in combination with conventional therapy may increase the risk of unwanted interactions, we investigated the possible genotoxicity of a water-soluble form of the dry root of P. ginseng (2.5, 5.0 or 10.0 mg/mL) and its ability to protect against the genotoxicity of doxorubicin (DOX; 0.125 mg/mL) by using the Drosophila melanogaster wing somatic mutation and recombination test (SMART) with standard and high-bioactivation crosses of flies. Panax ginseng was not genotoxic at the concentrations tested, whereas DOX-induced genotoxicity in marker-heterozygous flies resulted mainly from mitotic recombination. At low concentrations, P. ginseng had antirecombinogenic activity that was independent of the concentration of extract used. Recombination events may promote cancer, but little is known about the ability of P. ginseng to inhibit such recombination or modulate DNA repair mechanisms.

show abstract

Cytochrome P450 phenotypic ratios for predicting herb‐drug interactions in humans

Abstract: Single-time point phenotypic metabolic ratios may provide a practical means of predicting CYP-mediated herb-drug interactions in humans.

Cited by 319 publications

References 59 publications

Garlic extract induces intestinal P-glycoprotein, but exhibits no effect on intestinal and hepatic CYP3A4 in humans

Garlic extract induces intestinal P-glycoprotein, but exhibits no effect on intestinal and hepatic CYP3A4 in humans

Gender-specific induction of cytochrome P450s in nonylphenol-treated FVB/NJ mice

Protection by Panax ginseng C.A. Meyer against the genotoxicity of doxorubicin in somatic cells of Drosophila melanogaster

Contact Info

Product

Resources

About