Intersection of the Roles of Cytochrome P450 Enzymes with Xenobiotic and Endogenous Substrates: Relevance to Toxicity and Drug Interactions

Guengerich, F. Peter

doi:10.1021/acs.chemrestox.6b00226

Cited by 112 publications

(81 citation statements)

References 94 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The CYP enzymes comprise a very large superfamily, with 57 individual human forms identified. Of these CYP forms, approximately 10 members in the families CYP1, CYP2 and CYP3 catalyze the oxidation of xenobiotics to a significant degree (Testa et al, 2012;Guengerich 2017). CYPs are most abundantly expressed in the liver, but they are also present in other barrier tissues such as the gastrointestinal tract, lung, skin, kidney and nose epithelium (Sevior et al, 2012;Zanger and Schwab, 2013).…”

Section: Introductionmentioning

confidence: 99%

Development of new Coumarin-based profluorescent substrates for human cytochrome P450 enzymes

et al. 2018

View full text Add to dashboard Cite

1. Cytochrome P450 (CYP) enzymes constitute an essential xenobiotic metabolizing system that regulates the elimination of lipophilic compounds from the body. Convenient and affordable assays for CYP enzymes are important for assessing these metabolic pathways. 2. In this study, 10 novel profluorescent coumarin derivatives with various substitutions at carbons 3, 6 and 7 were developed. Molecular modeling indicated that 3phenylcoumarin offers an excellent scaffold for the development of selective substrate compounds for various human CYP forms, as they could be metabolized to fluorescent 7-hydroxycoumarin derivatives. Oxidation of profluorescent coumarin derivatives to fluorescent metabolites by 13 important human liver xenobiotic-metabolizing CYP forms was determined by enzyme kinetic assays. 3. Four of the coumarin derivatives were converted to fluorescent metabolites by CYP1 family enzymes, with 6-methoxy-3-(4-trifluoromethylphenyl)coumarin being oxidized selectively by CYP1A2 in human liver microsomes. Another set of four compounds were metabolized by CYP2A6 and CYP1 enzymes. 7-Methoxy-3-(3methoxyphenyl)coumarin was oxidized efficiently by CYP2C19 and CYP2D6 in a nonselective fashion. 4. The advantages of the novel substrates were 1) an excellent signal-to-background ratio, 2) selectivity for CYP1 forms, and 3) convenient multiwell plate measurement, allowing for precise determination of potential inhibitors of important human hepatic forms CYP1A2, CYP2C19 and CYP2D6.

show abstract

Section: Introductionmentioning

confidence: 99%

Development of new Coumarin-based profluorescent substrates for human cytochrome P450 enzymes

et al. 2018

View full text Add to dashboard Cite

show abstract

“…The cytochrome P450 (P450, CYP)‐dependent monooxygenase system consists of a group of heme‐containing proteins responsible for the detoxication and bioactivation of drugs, carcinogens, and pesticides. The monooxygenase system is also responsible for the metabolism of fatty acids, vitamins, and steroids . P450 enzymes are highly responsive to the inducing and inhibitory effects of foreign chemicals that humans may be exposed to.…”

Section: Introductionmentioning

confidence: 99%

Effects of tebuconazole on cytochrome P450 enzymes, oxidative stress, and endocrine disruption in male rats

Yang

Liu

Liao

et al. 2018

Environmental Toxicology

View full text Add to dashboard Cite

The major objective of the present study was to determine the ability of a triazole fungicide tebuconazole to induce cytochrome P450-dependent monooxygenases, oxidative stress, and endocrine-disrupting activity using male rats treated with tebuconazole at 10, 25, and 50 mg/kg p.o. once daily for 28 days. In liver, tebuconazole dose-dependently increased microsomal contents of cytochrome P450 and cytochrome b and the activities of NADPH-cytochrome P450 reductase, 7-ethoxyresorufin O-deethylase, methoxyresorufin O-demethylase, pentoxyresorufin O-dealkylase, 7-ethoxycoumarin O-deethylase, aniline hydroxylase, and erythromycin N-demethylase. In kidney, tebuconazole increased 7-ethoxycoumarin O-deethylase activity without affecting other monooxygenase activities. In marked contrast to liver and kidney, tebuconazole decreased testicular 7-ethoxyresorufin O-deethylase, methoxyresorufin O-demethylase, 7-ethoxycoumarin O-deethylase, aniline hydroxylase, and erythromycin N-demethylase activities. The results of immunoblot analysis of liver microsomes of controls and tebuconazole-treated rats revealed that tebuconazole induced CYP1A1/2, CYP2B1/2, CYP2E1, and CYP3A proteins in liver. Additions of tebuconazole to liver microsomes inhibited microsomal 7-ethoxycoumarin O-deethylase activity in vitro (IC = 1.50-1.69 µM). Treatment of rats with tebuconazole decreased glutathione content and increased glutathione S-transferase, superoxide dismutase, catalase, and glutathione peroxidase activities in liver; increased superoxide dismutase activities in kidney and testis; but decreased glutathione S-transferase activity in testis. Treatments with tebuconazole decreased serum testosterone concentration and cauda epididymal sperm count. The present study demonstrates that tebuconazole induces a multiplicity of CYPs and oxidative stress in liver; inhibits testicular P450 and glutathione S-transferase activities; and produces anti-androgenic effects in male rats.

show abstract

“…The steroidogenic P450s are particularly important, and homozygous or dual heterozygous deficiencies are often debilitating (2,4). P450 enzymes also have major roles in the metabolism of exogenous (xenobiotic) chemicals, including drugs and carcinogens (3), and some P450s oxidize both endogenous and xenobiotic substrates (5).…”

mentioning

confidence: 99%

Kinetic processivity of the two-step oxidations of progesterone and pregnenolone to androgens by human cytochrome P450 17A1

Gonzalez¹,

Guengerich

2017

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Cytochrome P450 (P450, CYP) 17A1 plays a critical role in steroid metabolism, catalyzing both the 17α-hydroxylation of pregnenolone and progesterone and the subsequent 17α,20-lyase reactions to form dehydroepiandrosterone (DHEA) and androstenedione (Andro), respectively, critical for generating glucocorticoids and androgens. Human P450 17A1 reaction rates examined are enhanced by the accessory protein cytochrome (), but the exact role of in P450 17A1-catalyzed reactions is unclear as are several details of these reactions. Here, we examined in detail the processivity of the 17α-hydroxylation and lyase steps. did not enhance reaction rates by decreasing the rates of any of the steroids. Steroid binding to P450 17A1 was more complex than a simple two-state system. Pre-steady-state experiments indicated lag phases for Andro production from progesterone and for DHEA from pregnenolone, indicating a distributive character of the enzyme. However, we observed processivity in pregnenolone/DHEA pulse-chase experiments. ()-Orteronel was three times more inhibitory toward the conversion of 17α-hydroxypregnenolone to DHEA than toward the 17α-hydroxylation of pregnenolone. IC values for ()-orteronel were identical for blocking DHEA formation from pregnenolone and for 17α-hydroxylation, suggestive of processivity. Global kinetic modeling helped assign sets of rate constants for individual or groups of reactions, indicating that human P450 17A1 is an inherently distributive enzyme but that some processivity is present, some of the 17α-OH pregnenolone formed from pregnenolone did not dissociate from P450 17A1 before conversion to DHEA. Our results also suggest multiple conformations of P450 17A1, as previously proposed on the basis of NMR spectroscopy and X-ray crystallography.

show abstract

Intersection of the Roles of Cytochrome P450 Enzymes with Xenobiotic and Endogenous Substrates: Relevance to Toxicity and Drug Interactions

Cited by 112 publications

References 94 publications

Development of new Coumarin-based profluorescent substrates for human cytochrome P450 enzymes

Development of new Coumarin-based profluorescent substrates for human cytochrome P450 enzymes

Effects of tebuconazole on cytochrome P450 enzymes, oxidative stress, and endocrine disruption in male rats

Kinetic processivity of the two-step oxidations of progesterone and pregnenolone to androgens by human cytochrome P450 17A1

Contact Info

Product

Resources

About