20-Hydroxylation is the CYP-dependent and retinoid-inducible leukotriene B4 inactivation pathway in human and mouse skin cells.
Metabolic inactivation of leukotriene B4 (LTB4) is an innate mechanism to resolve tissue inflammation. We studied the nine Cyp4f genes in the mouse genome, measuring cutaneous transcript levels by real-time polymerase chain reaction, and LTB4 metabolism in mouse and human skin. Transcripts arising from Cyp4f13 and 4f16 ranked most abundant, Cyp4f14, 4f17, and 4f37 ranked least abundant, and Cyp4f18 and 4f39 ranked intermediate. Those from Cyp4f15 and Cyp4f40 were highly variable or too low to measure in some animals. Retinoic acid exposure induced microsomal LTB4 hydroxylation activities in mouse and human skin cells. Two NADPH-dependent LTB4 metabolites eluted identically with 20-OH and 20-COOH LTB4 reference standards. Collision induced dissociation of the precursor ion m/z 351 confirmed that LTB4 products from CYP4F3A and human epidermal keratinocytes are identical structurally to 20-OH LTB4. We conclude 20-hydroxylation is the major CYP-dependent LTB4 inactivation pathway in skin; this retinoid-inducible metabolic pathway has capacity to modulate tissue levels of pro-inflammatory lipids.
Du
Liping
L
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA.
Yin
Huiyong
H
Morrow
Jason D
JD
Strobel
Henry W
HW
Keeney
Diane S
DS
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003580:Cytochromes / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D016133:Polymerase Chain Reaction; D012176:Retinoids / Q000494:pharmacology*; D012867:Skin / Q000166:cytology / Q000378:metabolism*
D003580:Cytochromes; D012176:Retinoids; D007975:Leukotriene B4