The Effects of Formaldehyde on Cytochrome P450 Isoform Activity in Rats

Abstract

Formaldehyde (FA) is an occupational and indoor pollutant. Long-term exposure to FA can irritate the respiratory mucosa, with potential carcinogenic effects on the airways. The effects of acute FA poisoning on the activities of CYP450 isoforms CYP1A2, CYP2C11, CYP2E1, and CYP3A2 were assessed by determining changes in the pharmacokinetic parameters of the probe drugs phenacetin, tolbutamide, chlorzoxazone, and testosterone, respectively. Rats were randomly divided into three groups: control, low FA dose (exposure to 110 ppm for 2 h for 3 days), and high FA dose (exposure to 220 ppm for 2 h for 3 days). A mixture of the four probe drugs was injected into rats and blood samples were taken at a series of time points. Plasma concentrations of the probe drugs were measured by HPLC. The pharmacokinetic parameters t1/2, AUC(0−t), and Cmax of tolbutamide, chlorzoxazone, and testosterone increased significantly in the high dose versus control group (P < 0.05), whereas the CL of chlorzoxazone and testosterone decreased significantly (P < 0.05). However, t1/2, AUC(0−t), and Cmax of phenacetin decreased significantly (P < 0.05), whereas the CL of phenacetin increased significantly (P < 0.05) compared to controls. Thus, acute FA poisoning suppressed the activities of CYP2C11, CYP2E1, and CYP3A2 and induced the activity of CYP1A2 in rats. And the change of CYP450 activity caused by acute FA poisoning may be associated with FA potential carcinogenic effects on the airways.

Synergistic Effect of Endogenous and Exogenous Aldehydes on Doxorubicin Toxicity in Yeast

“…Interestingly, the CYP3A family has been shown to metabolize doxorubicin and drugs that inhibit CYP3A results in elevated plasma concentration of doxorubicin [ 31 ]. It is also possible that formaldehyde coadministered with doxorubicin reduces the activity of CYP2C11 enzyme which results in elevated levels of doxorubicin [ 32 – 34 ].…”

Stereoisomers of octahydrocurcumin, the hydrogenated metabolites of curcumin, display stereoselective activity on the CYP2E1 enzyme in L-02 cells

“…The CYP cocktail substrate solutions consisted of different CYP enzyme substrates, including phenacetin (100 μM) for CYP1A2, coumarin (60 μM) for CYP2A6, diclofenac (90 μM) for CYP2C9, paclitaxel (20 μM) for CYP2C8, testosterone (100 μM) for CYP3A4, and chlorzoxazone (90 μM) for CYP2E1. [37][38][39][40] The UGT substrate solutions were prepared with 4-methylumbelliferone (100 μM) as the nonspecific probe substrate for UGTs alone. 41 2.5.4 HPLC analysis.…”

“…[37][38][39][40] An aliquot (25 μl) of the sample was analyzed by HPLC and detected at 254 nm for APAP (a metabolite of phenacetin), 254 or 320 nm for 7-hydroxycoumarin (a metabolite of coumarin), 254 or 280 nm for 4′hydroxydiclofenac (a metabolite of diclofenac), 229 or 280 nm for 6α-hydroxypaclitaxel (a metabolite of paclitaxel), 245 nm for 6β-hydroxytestosterone (a metabolite of testosterone), 254 or 287 nm for 6-hydroxychlorzoxazone (a metabolite of chlorzoxazone), and 316 nm for 4-methylumbelliferone-β-D-glucuronide (a metabolite of 4-methylumbelliferone). [37][38][39][40] 2.5.5 RT-PCR analysis. Real-time PCR was performed with ChamQ Universal SYBR qPCR Master Mix according to the manufacturer's instructions using a CFX 96 Real-Time PCR Detection System (Bio-Rad, America).…”

Beyond the label: current evidence and future directions for the interrelationship between electronic cigarettes and mental health

“…In addition to nicotine, carbonyls may also influence metabolism. For instance, acrolein has been found to inhibit CYP450 enzymes ( 173 ), and formaldehyde specifically reduces the levels of CYP2C11, CYP2E1, and CYP3A2, but increases CYP1A2, in male rats ( 166 ). Interestingly, the effects of formaldehyde on enzymatic activity led to decreased testosterone (steroid hormone) and chlorzoxazone (muscle relaxant) clearance, but increased phenacetin (analgesic) clearance ( 166 ).…”

“…For instance, acrolein has been found to inhibit CYP450 enzymes ( 173 ), and formaldehyde specifically reduces the levels of CYP2C11, CYP2E1, and CYP3A2, but increases CYP1A2, in male rats ( 166 ). Interestingly, the effects of formaldehyde on enzymatic activity led to decreased testosterone (steroid hormone) and chlorzoxazone (muscle relaxant) clearance, but increased phenacetin (analgesic) clearance ( 166 ). Propylene glycol has further been shown to inhibit CYP2E1, leading to decreased chlorzoxazone clearance by greater than 80% in male mice ( 172 ).…”