1-Aminobenzotriazole-Induced Destruction of Hepatic and Renal Cytochromes P450 in Male Sprague-Dawley Rats

1-Aminobenzotriazole (ABT) is a suicide substrate of both hepaticand pulmonary cytochromes P450. The present studies were designedto compare the effects of ABT on hepatic and renal metabolism.Hepatic and renal microsomes and cytosol were prepared frommale Sprague-Dawley rats following ABT pretreatment (0–100mg/kg ip) for various times. Administration of 100 mg ABT/kgproduced profound reductions in P450 content in both liver andkidney within 2 hr; loss of P450 in both tissues persisted forat least 48 hours. ABT-induced destruction of P450 was dose-dependent.Maximal destruction of about 80% of total hepatic P450 occurredat dosages of ABT equal to or greater than 10 mg/kg. Maximaldestruction of about 80% of total renal P450 occurred at dosagesof ABT equal to or greater than 50 mg/kg. In vitro, ABT rapidlyand efficiently destroyed P450 in both hepatic and renal microsomesprepared from naive male Sprague-Dawley rats. Incubation ofhepatic or renal microsomes in vitro with ABT produced detectabledestruction of P450 within 5 min. Maximal destruction of P450occurred within 10 min in both hepatic and renal microsomesduring in vitro incubation with ABT. ABT-induced destructionof P450 in vitro was concentration-dependent. For hepatic microsomes,maximal destruction of about 70% of P450 required concentrationsof ABT equal to or greater than 10 mM. For renal microsomes,maximal destruction of about 80% of P450 required concentrationsof ABT equal to or greater than 10 mM. In both liver and kidney,only P450 content and P450-dependent activities were significantlydecreased. Cytochrome b₅, NADPH cytochrome c reductase, glutathioneS-transferase, glucuronyl transferase, and reduced glutathionecontents were unaltered. These data suggest that ABT selectivelyand effectively destroys both hepatic and renal P450. ABT maybe a useful tool to probe the potential role of P450 in thebioactivation of certain compounds.     

Inhibition of Cytochromes P450: Existing and New Promising Therapeutic Targets

Mammalian cytochromes P450 have been shown to play highly important roles in the metabolism of drugs and xenobiotics as well as in the biosynthesis of a variety of endogenous compounds, many of them displaying hormonal function. The role of P450s as therapeutic targets is still inadequately recognized although several P450 inhibitors became efficient drugs that even reached blockbuster status. Here, we try to give a comprehensive overview on cytochromes P450s, which are already well-established targets – particularly focussing on the treatment of infectious diseases, metabolic disorders and cancer – and on those, which have a high potential to become successful targets. In addition, the design of inhibitors of cytochromes P450 will be discussed.     

Effects of Induction and Inhibition of Cytochromes P450 on the Hepatotoxicity of Methapyrilene

The mechanisms by which the antihistamine drug methapyrilenecauses acute periportal hepatotoxicity in rats are not yet elucidated.This study investigated the effects of modulators of cytochromeP450 (CYP) activity on the hepatotoxicity of methapyrilene andalso the effect of methapyrilene on hepatic CYP. Pretreatmentof male Han Wistar rats with ß-naphthoflavone, phenobarbitone,butylated hydroxytoluene, piperonyl butoxide, Aroclor 1254,or cobalt protoporphyrin IX, agents known to modify hepaticCYP, all afforded some degree of protection against a hepatotoxicdose of methapyrilene (150 mg/kg x 3 days p.o.), as assessedby clinical chemistry and histology. Total hepatic CYP depletionby cobalt protoporphyrin IX treatment indicated CYP-mediatedbioactivation was a prerequisite for methapyrilene-induced hepatotoxicity.Protection against hepatic damage was strongly associated withß-naphthoflavone induction of CYP1A and phenobarbitone-associatedCYP2B induction. However, the role of CYP3A, which is constitutivelyexpressed in the liver and induced by piperonyl butoxide, butylatedhydroxytoluene, or Aroclor 1254, was unclear. Modulation ofFAD monooxgenase activity by methimazole pretreatment was notassociated with increased methapyrilene-induced hepatotoxicity.Methapyrilene treatment alone specifically decreased microsomalenzyme activity markers for CYP2C11, CYP3A, and CYP2A and pretreatmentwith all the hepatic enzyme-inducing agents specifically preventedthe loss of CYP2C11. Together this suggested that CYP2C11 wasresponsible for the suicide substrate bioactivation of methapyrileneand the toxicologic outcome largely relied upon an abundanceof detoxifying enzymes present in the liver.     

Isopropanol 13-Week Vapor Inhalation Study in Rats and Mice with Neurotoxicity Evaluation in Rats

This study was conducted to evaluate the possible subchronictoxicity as well as neurobehavioral effects of isopropanol,a widely used industrial and commercial solvent. Five groups,each containing 10 Fischer 344 rats/sex and 10 CD-I mice/sex,were exposed for 6 hr/day, 5 days/week, for 13 weeks to isopropanolvapor at concentrations of 0 (control), 100, 500, 1500, or 5000ppm. An additional 15 rats/sex were assigned to the 0, 500,1500, and 5000 ppm groups for assessment of neurobehavioralfunction. No exposure-related mortalities occurred during thestudy. The narcotic effects of isopropanol were noted only duringexposures at 1500 and 5000 ppm. These signs, noted during exposures,were typically absent following exposures. The only clinicalsigns observed following exposures included swollen perioculartissue, perinasal encrustation, and ataxia for rats of the 5000ppm group. Neurobehavioral evaluations indicated no changesin any of the parameters of the functional observational battery;however, increased motor activity for female rats in the 5000ppm group was noted at Weeks 9 and 13. Decreases in body weightand body weight gain were observed for rats of the 5000 ppmgroup at the end of the first week of exposure. During the remainingweeks, increases in body weight and/or body weight gain wereobserved for rats of the 1500 and 5000 ppm groups. No exposure-relatedeffects on body weight were noted for male mice; however, increasedbody weight and body weight gain were observed for female miceof the 5000 ppm group. Increases or decreases in food and waterconsumption generally corresponded to changes in body weightand body weight gain. Various changes in clinical pathologyparameters were observed for rats and female mice of the 5000ppm group. The only organ weight effect noted was an increasedrelative liver weight in both sexes of rats of and female miceof the 5000 ppm group. At necropsy, three were no gross lesionsdetermined to be exposure related. Furthermore, the only microscopicchange observed was hyaline droplets within the kidneys of allmale rats (including controls). The size and frequency of thehyaline droplets were increased for the isopropanol exposuregroups compared to the control group. These differences werenot clearly concentration related, although this microscopicchange was most pronouced in the high-concentration group. Neuropatholo0gicexamination revealed no exposure-related lesions in the centralor peripheral nervous system of exposed rats. Thus, repeatedexposures to isopropanol for 13 weeks produced toxic effctsonly at the highest concentration and a kidney change in malerats of unknown biological significance.     

Cytochromes P450 in the bioactivation of chemicals

The initial view that the cytochrome P450 enzyme system functions simply in the deactivation of xenobiotics is anachronistic on the face of mounting evidence that this system can also transform many innocuous chemicals to toxic products. However, not all xenobiotic-metabolising cytochrome P450 subfamilies show the same propensity in the bioactivation of chemicals. For example, the CYP2C, 2B and 2D subfamilies play virtually no role in the bioactivation of toxic and carcinogenic chemicals, whereas the CYP1A, 1B and 2E subfamilies are responsible for the bioactivation of the majority of xenobiotics. Electronic and molecular structural features of organic chemicals appear to predispose them to either bioactivation by one cytochrome P450 enzyme or deactivation by another. Consequently, the fate of a chemical in the body is largely dependent on the cytochrome P450 profile at the time of exposure. Any factor that modulates the enzymes involved in the metabolism of a certain chemical will also influence its toxicity and carcinogenicity. For example, many chemical carcinogens bioactivated by CYP1, on repeated administration, selectively induce this family, thus exacerbating their carcinogenicity. CYP1 induction potency by chemicals appears to be determined by a combination of their molecular shape and electron activation. The function of cytochromes P450 in the bioactivation of chemicals is currently being exploited to design systems that can be used clinically to facilitate the metabolic conversion of prodrugs to their biologically-active metabolites in cells that poorly express them, such as tumour cells, in the so-called gene-directed prodrug therapy.     

Cytochromes P450 in brain: function and significance

The presence and activity of cytochromes P450 in brain regions and various brain cells have been extended and advanced over the last five years covered by this review. Using in situ hybridization and immunohistochemical techniques, many cytochrome P450 enzymes have been demonstrated to be present in brain and to have a regional rather than universal distribution. Many of these various cytochromes P450 have been shown to catalyze the metabolism of neurosteroids as well as other biologically significant compounds in brain. In addition, many cytochrome P450 enzymes have been implicated in the metabolism of psychoactive drugs such as neuroleptics and antidepressants. The regulation of cytochrome P450 expression has been studied at greater detail, the regulation of aromatase being a prominent example during the last five years.     

Endo-Xenobiotic Crosstalk and the Regulation of Cytochromes P450

Evolution has provided organisms with an elaborate defense system against foreign compounds and against the accumulation of potentially toxic endogenous molecules, e.g. bile acids. Cytochromes P450 represent an important group of enzymes in this system. This article describes experiments started in the 1970's in Dallas on the coordination of heme and cytochrome P450 synthesis and how these studies evolved over the years into a concept of molecular links between xenobiotic metabolism and endogenous pathways of sterol, lipid, bile acid and energy homeostasis.     

Dimethylethanolamine: Acute, 2-Week, and 13-Week Inhalation Toxicity Studies in Rats

Dimethylethanolamine (DMEA) is a volatile, water-soluble aminethat has applications in the chemical and pharmaceutical industries.These studies evaluated the acute and subchronic inhalationtoxicity of DMEA. Acute (4-hr) exposures of Wistar rats to DMEAvapor resulted in an LC5O value (95% confidence limits) of 1641(862–3125)ppm. Clinical signs of nasal and ocular irritation, respiratorydistress, and body weight loss were observed in rats exposedto 1668 ppm DMEA and higher. In the 2-week study, F-344 ratsexposed to 98, 288, or 586 ppm DMEA for 9 days (6 hr/day) duringan 11-day period also exhibited signs of respiratory and ocularirritation (except the 98 ppm group). All animals of the 586ppm group and 4 of 15 male rats of the 288 ppm group died. Bodyweight values for the 288 ppm group were reduced to about 75%of preexposure values, while the 98 ppm group gained 35% lessweight than controls. Statistically significant differencesin clinical pathology parameters (288 ppm group) and in organweight values (288 and 98 ppm groups) probably resulted fromthe decreased food consumption and not from specific targetorgan toxicity. In the groups evaluated histologically (the98 and 288 ppm groups) the eye and nasal mucosa were the primarytarget organs. In the 13-week subchronic study, F-344 rats wereexposed to 0, 8, 24, or 76 ppm DMEA for 6 hr/day, 5 days/weekfor 13 weeks. The principal exposure-related changes were transientcorneal opacity in the 24 and 76 ppm groups; decreased bodyweight gain for the 76 ppm group; and histopathologic lesionsof the respiratory and olfactory epithelium of the anteriornasal cavity of the 76 ppm group and of the eye of several 76ppm group females. Rats maintained for a 5-week recovery periodonly exhibited histological lesions of the nasal tissue, withthe lesions being decreased in incidence and severity. DMEAacts primarily as an ocular and upper respiratory tract irritantand toxicant at vapor concentrations of 76 ppm, while 24 ppmor less produced no biologically significant toxicity in rats.Thus, 24 ppm was considered to be the no-observable-effect level.     

Evaluation of Inhibition Selectivity for Human Cytochrome P450 2A Enzymes

Cytochrome P450 (P450) enzymes are mixed-function oxidases that catalyze the metabolism of xenobiotics and endogenous biochemicals. Selective inhibitors are needed to accurately distinguish the contributions of individual P450 enzymes in the metabolism of drugs and the activation of procarcinogens in human tissues, but very frequently these enzymes have substantial overlapping selectivity. We evaluated a chemically diverse set of nine previously identified CYP2A6 inhibitors to determine which are able to discriminate between human CYP2A enzymes CYP2A6 and the 94%-identical CYP2A13 enzyme. Inhibitor binding to recombinant purified enzyme was evaluated, and affinities were determined. K(i) values were determined for inhibition of p-nitrophenol 2-hydroxylation, a reaction accomplished by CYP2A13 and CYP2A6 with more similar catalytic efficiencies (k(cat)/K(m) 0.19 and 0.12 μM(-1) · min(-1), respectively) than hydroxylation of the classic substrate coumarin (0.11 and 0.53 μM(-1) · min(-1), respectively). Of the nine compounds assayed, only tranylcypromine and (R)-(+)-menthofuran had a greater than 10-fold preference for CYP2A6 inhibition versus CYP2A13 inhibition. Most compounds evaluated [tryptamine, 4-dimethylaminobenzaldehyde, phenethyl isothiocyanate, β-nicotyrine, (S)-nicotine, and pilocarpine] demonstrated only moderate or no preference for inhibition of one CYP2A enzyme over the other. However, 8-methoxypsoralen has a 6-fold lower K(i) for CYP2A13 than for CYP2A6. This information is useful to inform reinterpretation of previous data with these inhibitors and to guide future studies seeking to determine which human CYP2A enzyme is responsible for the in vivo metabolism of compounds in human tissues expressing both enzymes.     

Chlorpyrifos: A 13-Week Nose-Only Vapor Inhalation Study in Fischer 344 Rats

Fischer 344 rats were exposed by the nose-only inhalation routeto chlorpyrifos vapors at concentrations of 0, 5.2, 10.3, or20.6 ppb, 6 hr/day, 5 days/week for 13 weeks. The exposure concentrationswere limited by the low vapor pressure of chlorpyrifos (theoreticalmaximum vapor concentration of 25 ppb at 25?C). No treatment-relatedsigns of toxicity or changes in body weights were detected duringthe course of the study. Unnalysis, hematology, clinical chemistry,organ weights, gross pathologic, and histopathologic evaluationswere performed at the end of the study with no treatment-relatedeffects observed. In addition, no differences from controlswere noted in plasma, red blood cell, or brain cholinesteraseactivities. The results of this study indicate that the no-observed-effectlevel for chlorpyrifos vapor was the highest attainable concentration,20.6 ppb, in male and female Fischer 344 rats.     

Inhibition of carcinogen-bioactivating cytochrome P450 1 isoforms by amiloride derivatives

We examined the effects of amiloride derivatives, especially 5-(N-ethyl-N-isopropyl)amiloride (EIPA), on the activity of cytochrome P450 (CYP) 1 isoforms, known to metabolize carcinogenic polycyclic aromatic hydrocarbons (PAHs), such as benzo(a)pyrene (BP), into mutagenic metabolites and whose cellular expression can be induced through interaction of PAHs with the arylhydrocarbon receptor. EIPA was found to cause a potent and dose-dependent inhibition of CYP1-related ethoxyresorufine O-deethylase (EROD) activity in both liver cells and microsomes. It also markedly reduced activity of human recombinant CYP1A1 enzyme through a competitive mechanism; activities of other human CYP1 isoforms, i.e. CYP1A2 and CYP1B1, were also decreased. However, EIPA did not affect BP-mediated induction of CYP1A1 mRNA and protein levels in rat liver cells, likely indicating that EIPA does not block activation of the arylhydrocarbon receptor by PAHs. Inhibition of CYP1 activity by EIPA was associated with a decreased metabolism of BP, a reduced formation of BP-derived DNA adducts and a diminished BP-induced apoptosis in liver cells. The present data suggest that amiloride derivatives, such as EIPA, may be useful for preventing toxicity of chemical carcinogens, such as PAHs, through inhibition of CYP1 enzyme activity.     

Cytochromes P450--a family of proteins and scientists-understanding their relationships

The unifying thread of this review involves NADPH-cytochrome P450 reductase (CYPOR), the microsomal enzyme responsible for transferring electrons to cytochromes P450, as well as several other monooxygenase systems, a lifelong interest of the corresponding author. The intersection of her research with that of Dr. David Kupfer, their resulting collaboration, and the beginning of a long-standing study of fatty acid- and eicosanoid-metabolizing cytochromes P450 (CYP4A gene subfamily), including the role of cytochrome b5, will be reported. The culmination of this interest now involves purification and characterization of the human mutants of CYPOR that have been implicated in pathologies, such as Antley-Bixler syndrome.     

Nasal Toxicity of Manganese Sulfate and Manganese Phosphate in Young Male Rats Following Subchronic (13-Week) Inhalation Exposure

Growing evidence suggests that nasal deposition and transport along the olfactory nerve represents a route by which inhaled manganese and certain other metals are delivered to the rodent brain. The toxicological significance of olfactory transport of manganese remains poorly defined. In rats, repeated intranasal instillation of manganese chloride results in injury to the olfactory epithelium and neurotoxicity as evidenced by increased glial fibrillary acidic protein (GFAP) concentrations in olfactory bulb astrocytes. The purpose of the present study was to further characterize the nasal toxicity of manganese sulfate (MnSO₄) and manganese phosphate (as hureaulite) in young adult male rats following subchronic (90-day) exposure to air, MnSO₄ (0.01, 0.1, and 0.5 mg Mn/m³), or hureaulite (0.1 mg Mn/m³). Nasal pathology, brain GFAP levels, and brain manganese concentrations were assessed immediately following the end of the 90-day exposure and 45 days thereafter. Elevated end-of-exposure olfactory bulb, striatum, and cerebellum manganese concentrations were observed following MnSO₄ exposure to ≥0.01, ≥0.1, and 0.5 mg Mn/m³, respectively. Exposure to MnSO₄ or hureaulite did not affect olfactory bulb, cerebellar, or striatal GFAP concentrations. Exposure to MnSO₄ (0.5 mg Mn/m³) was also associated with reversible inflammation within the nasal respiratory epithelium, while the olfactory epithelium was unaffected by manganese inhalation. These results confirm that high-dose manganese inhalation can result in nasal toxicity (irritation) and increased delivery of manganese to the brain; however, we could not confirm that manganese inhalation would result in altered brain GFAP concentrations.     

Evaluation of Six Proton Pump Inhibitors As Inhibitors of Various Human Cytochromes P450: Focus on Cytochrome P450 2C19

Six proton pump inhibitors (PPIs), omeprazole, lansoprazole, esomeprazole, dexlansoprazole, pantoprazole, and rabeprazole, were shown to be weak inhibitors of cytochromes P450 (CYP3A4, -2B6, -2D6, -2C9, -2C8, and -1A2) in human liver microsomes. In most cases, IC(50) values were greater than 40 μM, except for dexlansoprazole and lansoprazole with CYP1A2 (IC(50) = ～8 μM) and esomeprazole with CYP2C8 (IC(50) = 31 μM). With the exception of CYP2C19 inhibition by omeprazole and esomeprazole (IC(50) ratio, 2.5 to 5.9), there was no evidence for a marked time-dependent shift in IC(50) (IC(50) ratio, ≤2) after a 30-min preincubation with NADPH. In the absence of preincubation, lansoprazole (IC(50) = 0.73 μM) and esomeprazole (IC(50) = 3.7 μM) were the most potent CYP2C19 inhibitors, followed by dexlansoprazole and omeprazole (IC(50) = ～7.0 μM). Rabeprazole and pantoprazole (IC(50) = ≥25 μM) were the weakest. A similar ranking was obtained with recombinant CYP2C19. Despite the IC(50) ranking, after consideration of plasma levels (static and dynamic), protein binding, and metabolism-dependent inhibition, it is concluded that omeprazole and esomeprazole are the most potent CYP2C19 inhibitors. This was confirmed after the incubation of the individual PPIs with human primary hepatocytes (in the presence of human serum) and by monitoring their impact on diazepam N-demethylase activity at a low concentration of diazepam (2 μM). Data described herein are consistent with reports that PPIs are mostly weak inhibitors of cytochromes P450 in vivo. However, two members of the PPI class (esomeprazole and omeprazole) are more likely to serve as clinically relevant inhibitors of CYP2C19.     

Cytochromes P450 and flavin monooxygenases--targets and sources of nitric oxide.

This article is a report on a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics and held at the Experimental Biology 01 meeting in Orlando, FL. The presentations addressed the mechanisms of inhibition and regulation of cytochrome P450 and flavin monooxygenase enzymes by nitric oxide. They also highlighted the consequences of these effects on metabolism of drugs and volatile amines as well as on important physiological parameters, such as control of blood pressure, renal ion transport, and steroidogenesis. This is achieved via regulation of P450-dependent prostacyclin, hydroxyeicosatetraenoic acid, and epoxyeicosatrienoic acid formation. Conversely, the mechanisms and relative importance of nitric oxide synthases and P450 enzymes in NO production from endogenous and synthetic substrates were also addressed.     

Propylene Glycol Monomethyl Ether: A 13-Week Inhalation Toxicity Study in Rats and Rabbits

Propylene Glycol Monomethyl Ether: A 13-Week Inhalation ToxicityStudy in Rats and Rabbits. Landry, T.D., Gushow, T.S. and Yano,B.L. (1983). Fundam. Appl. Toxicol. 3:627–630. Fischer344 rats (10/sex/exposure concentration) and New Zealand Whiterabbits (7/sex/exposure concentration) were exposed to 0, 300,1000, or 3000 ppm (0, 1.09, 3.62, or 10.9 mg/L) of propyleneglycol monomethyl ether (PGME) for 6 hr/da, 5 da/wk, for 13weeks. Minimal effects were observed in animals exposed to 3000ppm. Indications of a transient central nervous system depressionwere observed in rats and rabbits exposed to 3000 ppm. Therewere also small increases (6 to 8%) in mean relative liver weightsof 3000 ppm exposed male and female rats relative to controls.Minimal histologic effects were observed in the livers of 3000ppm exposed female rats. These were suggestive of hepatocellularhypertrophy but were without evidence of degenerative changes.There was an increase in the urinary pH of male rats exposedto 3000 ppm PGME for 4 weeks, but this was not evident after12 weeks of exposure. There was no indication of histopathologicaleffects in the kidneys of either species, and there were nohematological effects. No treatment-related effects were foundin either rats or rabbits exposed to 300 or 1000 ppm.     

Dipropylene Glycol Monomethyl Ether: A 13-Week Inhalation Toxicity Study in Rats and Rabbits

Dipropylene Glycol Monomethyl Ether. A 13-Week Inhalation Studyin Rats and Rabbits. LANDRY, T. D., AND YANO, B. L. (1984).Fundam. Appl. Toxicol. 4, 612–617. Fischer 344 rats (10/sex/exposureconcentration) and New Zealand White rabbits (7/sex/exposureconcentration) were exposed to 0, 15, 50, or 200 ppm (0, 91,303, or 1212 mg/m3) of dipropylene glycol monomethyl ether (DPGME)for 6 hr/day, 5 days/week for 13 weeks. Criteria of responseincluded general observations, body weights, clinical chemistry,hematology, urinalyses (rats only), necropsy, organ weights,and histopathology. There were no effects attributed to exposureto DPGME at any exposure concentration in either male or femalerats or rabbits. The highest concentration tested (200 ppm)was approximately 40% of a saturated DPGME atmosphere. Basedon the low vapor pressure of DPGME, and results in this 13-weekstudy, DPGME appears to have a low subchronic vapor inhalationtoxicity hazard.     

Oxidation of pyrene, 1-hydroxypyrene, 1-nitropyrene and 1-acetylpyrene by human cytochrome P450 2A13

Abstract

1.?The polycyclic hydrocarbons (PAHs), pyrene, 1-hydroxypyrene, 1-nitropyrene and 1-acetylpyrene, were found to induce Type I binding spectra with human cytochrome P450 (P450) 2A13 and were converted to various mono- and di-oxygenated products by this enzyme.

2.?Pyrene was first oxidized by P450 2A13 to 1-hydroxypyrene which was further oxidized to di-oxygenated products, i.e. 1,8- and 1,6-dihydroxypyrene. Of five other human P450s examined, P450 1B1 catalyzed pyrene oxidation to 1-hydroxypyrene at a similar rate to P450 2A13 but was less efficient in forming dihydroxypyrenes. P450 2A6, a related human P450 enzyme, which did not show any spectral changes with these four PAHs, showed lower activities in oxidation of these compounds than P450 2A13.

3.?1-Nitropyrene and 1-acetylpyrene were also found to be efficiently oxidized by P450 2A13 to several oxygenated products, based on mass spectrometry analysis.

4.?Molecular docking analysis supported preferred orientations of pyrene and its derivatives in the active site of P450 2A13, with lower interaction energies (U values) than observed for P450 2A6 and that several amino acid residues (including Ala-301, Asn-297 and Ala-117) play important roles in directing the orientation of these PAHs in the P450 2A13 active site. In addition, Phe-231 and Gly-329 were found to interact with pyrene to orient this compound in the active site of P450 1B1.

5.?These results suggest that P450 2A13 is one of the important enzymes that oxidizes these PAH compounds and may determine how these chemicals are detoxicated and bioactivated in humans.